Front cover: Composite of images from 30 research groups Photomontage created by M. Avella. Photo copyrights © SIGNALIFE 2013 by Abad, Arkowitz, Attard, Barbry, Bardoni, Bassilana, Besse, Braendle, Burel, Chaboissier, Chakrabanhu, Chassot, Collombat, Cseh, Descombes, Favery, Feral, Franco, Frendo, Fürthauer, Gaggioli, Gatti, Hofman, Hok, Hueber, Lalli, Lemichez, Luton, Magnaldo, Medioni, Meneguzzi, Marie, Martin, Nahon, Noselli, Panabières, Pegard, Poirié, Robichon, Rousset, Schedl, Studer, Thérond, Trabucchi, Virolle, V.O-Schilling

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TABLE OF CONTENT

SCIENTIFIC and ORGANIZING COMMITTEE ............................................................................................ 6

PROGRAM OVERVIEW ............................................................................................................................ 7

ORAL COMMUNICATIONS ...................................................................................................................... 9

Session I, Axis 1 Cellular Architecture of Signaling Pathways ................. 10

Invited Keynote Lecture : Yves Barral ............................................................................................ 11

Signalife Keynote : Bruno Antonny................................................................................................ 12

Presentation 1 : Emilie Andrio ....................................................................................................... 13

Presentation 2: Tamas Matusek .................................................................................................... 14

Session II, Axis 2 Plasticity and Signaling ........................................................ 15

Invited Keynote Lecture : Karine Clément ..................................................................................... 16

Signalife Keynote : Emmanuel Van Obberghen ............................................................................ 17

Presentation 1: Mathilde Clément ................................................................................................ 18

Presentation 2: Anne-Laure Hafner ............................................................................................... 19

Session III, Axis 3 Stress Signaling ............................................................... 20

Invited Keynote Lecture : Thomas Lahaye .................................................................................... 21

Signalife Keynote : Laetitia Perfus-Barbeoch ................................................................................ 22

Presentation 1: Johanna Chiche .................................................................................................... 23

Presentation 2: Carolina W Ribeiro ............................................................................................... 24

Session IV, Axis 4 Signaling in aging and disease Progression ........................ 25

Invited Keynote Lecture : Patrick Mehlen ..................................................................................... 26

Signalife Keynote : Pierre Leopold................................................................................................. 27

Presentation 1: Franck Ceppo ....................................................................................................... 28

Presentation 2: Julien Cherfils-Vicini ............................................................................................. 29

Session V, Axis 5 New principles in signaling and applications ............... 30

Invited Keynote Lecture : Klaus Hahn ........................................................................................... 31

Signalife Keynote : Franck Delaunay ............................................................................................. 32

Presentation 1: Benjamin Mauroy ................................................................................................ 33

Presentation 2: Rihab Loudhaief ................................................................................................... 34

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POSTERS Wine and Cheese Poster Session ..................................... 35

Poster Session I, Axis 1 Cellular Architecture of Signaling Pathways .................... 36

BOULAKIRBA Sonia 1.1 .................................................................................................................. 37

BOULTER Etienne 1.2 ..................................................................................................................... 38

FOUCHER Kevin 1.3 ....................................................................................................................... 39

GIORDANO Cécile 1.4 .................................................................................................................... 40

GIROUD Maude 1.5 ....................................................................................................................... 41

GORE Tanvi 1.6 .............................................................................................................................. 42

HARB Kawssar 1.7 .......................................................................................................................... 43

MESMIN Bruno 1.8 ........................................................................................................................ 44

Poster Session II, Axis 2 Plasticity and Signaling ........................................................ 45

BEN OTHMAN Nouha 2.1 .............................................................................................................. 46

CHASSOT Anne Amandine 2.2 ....................................................................................................... 47

LE THUC Ophélia 2.3 ...................................................................................................................... 48

MAGRINELLI Elia 2.4 ...................................................................................................................... 49

MORATAL Claudine 2.5 ................................................................................................................. 50

REINGOLD Victoria 2.6 ................................................................................................................... 51

VIEIRA Andhira 2.7 ......................................................................................................................... 52

VIOLLET Sébastien 2.8 ................................................................................................................... 53

Poster Session III, Axis 3 Stress Signaling ............................................................... 54

DANI Vincent 3.1 ........................................................................................................................... 55

LOUBIERE Camille 3.2 .................................................................................................................... 56

PRATX Loris 3.3 .............................................................................................................................. 57

ZUNINO Barbara 3.4 ...................................................................................................................... 58

Poster Session IV, Axis 4 Signaling in aging and disease Progression ........................ 59

ALBRENGUES Jean 4.1 ................................................................................................................... 60

DUBOIS Nicolas 4.2 ........................................................................................................................ 61

EL MAI Mounir 4.3 ..................................................................................................................... 62

ESTRACH Soline 4.4 ....................................................................................................................... 63

GACHE Yannick 4.5 ........................................................................................................................ 64

GILLERON Jérôme 4.6 .................................................................................................................... 65

GUAL Phillipe 4.7 ........................................................................................................................... 66

HINAULT Charlotte 4.8 .................................................................................................................. 67

LOUET Jean-François 4.9 ............................................................................................................... 68

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MARTIN Pauline 4.10 ..................................................................................................................... 69

MOURGUES Lucas 4.11.................................................................................................................. 70

POTTIER Anaïs 4.12 ........................................................................................................................ 71

PROD'HOMME Virginie 4.13 .......................................................................................................... 72

REPETTO Emanuela 4.14 ............................................................................................................... 73

ROUANET Sophie 4.15 ................................................................................................................... 74

TICHET Mélanie 4.16 ..................................................................................................................... 75

Poster Session V, Axis 5 New principles in signaling and applications .............. 76

CATOZZI Simona 5.1 ...................................................................................................................... 77

ZUBIOLO Alexis 5.2 ........................................................................................................................ 78

LIST OF PARTICIPANTS .......................................................................................................................... 79

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SCIENTIFIC and ORGANIZING COMMITTEE

President Stéphane Noselli

Executive Coordinators Martine Avella Harald Keller

Secretary Konstanze Beck

Axes Program organizers Robert Ballotti Florence Besse Christian Dani

Xavier Descombes Bruno Favery Pierre Frendo

Emmanuel Lemichez Thierry Magnaldo Stéphane Martin Michèle Studer Frédéric Bost

Emmanuel Van Obberghen Ellen Van Obberghen-Schilling

Chairmen/Woman Maximilian Fürthauer

Jean-Louis Nahon Thierry Magnaldo

Jean-François Tanti Florence Besse

CONTACT AND INFORMATION

Email : signalife-meeting@unice.fr

Many thanks to

Aguila F., Barone V., Beurtey S, Chavigny P., Genêt L., Khayachi A, Lantéri B., Leclef N., Llored A., Meira Da Silva C., Muller M. ,Szmidt S., the Université Nice Sophia Antipolis (UNS) Château logistic support and the UNS Communication service.

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PROGRAM OVERVIEW

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ORAL COMMUNICATIONS

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Session I, Axis 1 Cellular Architecture of Signaling Pathways

Chair : M. Fürthauer

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Invited Keynote Lecture : Yves Barral

Lateral diffusion barriers in endomembranes and their roles in cellular memory and ageing BARRAL Yves ETH Zurich, Institute of Biochemistry, Zurich, Switzerland (corresponding author : yves.barral@bc.biol.ethz.ch) Keywords : Ageing, Asymmetric cell division, Lateral diffusion barriers, Memory, Immunity Aging, first envisioned as a specialty of metazoans, also affects unicellular organisms, probably through very similar mechanisms across evolution. For example, budding yeast proliferates through asymmetric divisions, where the daughter cell buds from the surface of its mother. While daughter cells are born young, the mother cell ages at each division. This process, called replicative aging, offers exceptional conditions to observe aging of individual cells and characterize the molecular and cellular events associated with this process. It also offers the opportunity to investigate the mechanisms through which age is reset in the daughters. Over the last few years, we identified a number of lateral diffusion barriers in the plane of internal membranes at the mother-bud neck of yeast cells. These barriers, present in the endoplasmic reticulum (ER) and the nuclear envelope, limit the exchange of membrane-associated macromolecules between mother and bud. Remarkably, mutations abrogating these barriers impair the rejuvenation of buds, and extend the longevity of their mothers, indicating that they help maintaining age in the mother. We have used these observations to search for aging factors and investigate the processes in which they are normally involved. These studies suggest several remarkable conclusions: First, aging factors not only comprise damages, but also memory traces contributing to the individuation of the cell. Thus, individuation, or specification, of the cell appears tightly interlinked to its aging. Second, diffusion barriers are composed of specialized lipid domains and regulated as a function of stress and the nutritional status of the cell. Third, the selective permeability of the barrier allows cells to sort cargoes and confine only the appropriate ones in the aging compartment. Finally, I will provide evidence that the cell uses these features in a genomic immunity system to prevent the proliferation of DNA molecules of foreign origin. Aging might have emerged as a secondary effect of this immunity system.

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Signalife Keynote : Bruno Antonny

A new mechanism to control the distribution of cholesterol within cell organelles using the metabolic energy of phosphoinositides MESMIN Bruno (1), BIGAY Joëlle (1), MOSER VON FILSECK Joachim (1), LACAS-GERVAIS Sandra (2, DRIN Guillaume (1), ANTONNY Bruno (1) (1) Université de Nice et CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne Sophia Antipolis, France (2) Université de Nice, Centre Commun de Microscopie Appliquée, Nice, France (corresponding author : antonny@ipmc.cnrs.fr) Keywords : Cholesterol, Lipid transport, PI(4)P, Membrane Contact sites Vesicular transport necessarily induces the mixing of membranes of different lipid composition. Without active mechanisms, cellular organelles that are connected by membrane traffic pathways would loose their lipid identity. Here we describe a mechanism that helps to maintain a difference in lipid composition between two closely apposed organelles. Oxysterol-Binding Protein (OSBP) contains a PH domain that interacts with the Golgi phosphoinositide PI(4)P, a FFAT motif that interacts with the ER protein VAP-A and a lipid transfer domain (e.g. ORD). This architecture is suggestive of two activities: ER-Golgi tethering to make a membrane contact site, and lipid transfer. Using cellular and reconstitution experiments, we show that these two activities are coupled according to the following cycle: First, membrane tethering by the PH domain and the FFAT motif enables sterol transfer by the lipid transfer domain (ORD). Second, the transfer of sterol is coupled to back transfer of PI(4)P by the ORD. Last, PI(4)P after its back transfer is hydrolyzed in cis by the ER protein Sac1. This step makes the cycle irreversible and can drive forward sterol transfer when the amount of PI(4)P is sufficient or allow disruption of tethering when PI(4)P becomes limiting. Because other lipid transfer proteins display a similar architecture, the OSBP cycle might define a general mechanism whereby the metabolic energy of a phosphoinositide is used to maintain different levels of other lipid species between apposed organelles.

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Presentation 1 : Emilie Andrio

Control of Rac1 by HACE1 E3 ubiquitin ligase ANDRIO Emilie (1,2) *, LOTTE Romain (1,2,3) *, HAMAOUI Daniel (1,2), CHERFILS Jacqueline (3), BOST Frédéric (1,2), DOYE Anne (1,2), RUIMY Raymond (1,2,3), METTOUCHI Amel (1,2) and LEMICHEZ Emmanuel (1,2) *contributed equally to this work (1) INSERM U1065, C3M, 151 route St Antoine de Ginestière, Nice, France (2) Université de Nice Sophia-Antipolis, France (3) Laboratoire de Bactériologie, CHU, Nice, France (4) Laboratoire d'Enzymologie et Biochimie Structurales, Centre de Recherche de Gif, CNRS, Gif-sur-Yvette, France (corresponding author : lemichez@unice.fr) Keywords : Rho GTPases, Rac1, E3 ubiquitin ligase, HACE1 Rac1 belongs to the family of small GTPases, which control major cellular processes such as cell proliferation, survival, actin cytoskeleton organization and cell adhesion and migration. Rac1 also controls cell defenses against pathogens, notably by inducing inflammatory chemokines and ROS production. A number of bacterial toxins hijack cellular functions by targeting Rho GTPases in order to promote their invasion. The CNF1 toxin of uropathogenic Escherichia coli modifies the glutamine 61 of Rac1 into a glutamic acid residue leading to its constitutive activation. Nevertheless, activation of Rac1 sensitises it to poly-ubiquitylation and degradation by the Ubiquitin-proteasome system (UPS). Using properties of CNF1, we were able to identify a crucial role of the tumour suppressor HACE1, as an E3 ubiquitin-ligase that controls the stability of activated Rac1 (1). Our work should precisely determine how and whether HACE1 E3 ubiquitin ligase is a crucial regulator of Rac1 in cancer and infection. This work is supported by : Institut national de la santé et de la recherche médicale (INSERM), Université de Nice Sophia Antipolis (UNS), Agence Nationale de la Recherche (ANR), La Ligue Nationale contre le cancer 1. The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active Rac1. Torrino S, Visvikis O, Doye A, Boyer L, Stefani C, Munro P, Bertoglio J, Gacon G, Mettouchi A, Lemichez E. (2011) Dev Cell 21(5):959-65 Acknowledgement: LOUBIERE Camille, LOUBATIER Céline, DERENNE Sébastien for their kind help

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Presentation 2: Tamas Matusek

Secretion and exovesicle mediated transport of the Hedgehog morphogen is regulated by the ESCRT complex. MATUSEK Tamas (1), WENDLER Franz (1), FURTHAUER Maximilian (1), PIZETTE Sandrine (1), D’ANGELO Gisela (1) and THEROND Pascal (1) (1) UNS - CNRS UMR7277 - Inserm U1091, Institut de Biologie Valrose, Nice, France (corresponding author : therond@unice.fr) Keywords : Hedgehog, morphogen, ESCRT, exovesicles, Drosophila The cellular mechanisms that have evolved to extract and handle lipidated Hedgehogh (Hh) proteins in the spatial deployment of the signal in developing tissue is poorly understood and conflicting results have been published concerning the vehicle Hh uses for its long range delivery. Released Hh appears to be present in protein aggregates, and/or liposomal membrane compartments as a part of a lipoprotein complex or also in vesicular structure. However the possibility of Hh transport via membranous vesicles released by cells (also called exovesicles) has never been functionally explored. Exovesicles may be generated by plasma membrane budding or by fusion of multivesicular bodies (MVBs, an endocytic compartment) with the plasma membrane, leading to the release of MVB intraluminal vesicles into the extracellular space. As for plasma membrane budding, the formation of MVB intraluminal vesicles requires the severing of thin stalks of MVB-limiting membrane filled with cytosol. This type of budding requires a specialized machinery, the ESCRT (Endosomal Sorting Complexes Required for Transport) complex. This machinery is highly conserved but, surprisingly, its functional requirement for morphogen secretion in vivo has not been investigated. We used the Drosophila wing imaginal disc (WID) as a model system to investigate the role of ESCRT proteins and exovesicles in Hh secretion. Our study provides several firm lines of evidence to suggest that Hh secretion is dependent on ESCRT function. First, the blockade of ESCRT activity in Hh-producing cells in vivo led to the retention of Hh at the external surface of the secreting cells and a specific loss of Hh target expression. Second, we found Hh and ESCRTs at some distance from their source of production, spreading in common particles that can accumulate at the external surface of recipient cells expressing the Hh receptor. These findings reveal a novel function for ESCRT proteins in controlling morphogen activity. They also provide evidence for a previously unidentified mechanism for Hh release and intercellular communication.

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Session II, Axis 2 Plasticity and Signaling

Chair : J-L. Nahon

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Invited Keynote Lecture : Karine Clément

Gut microbiota and metabolic diseases CLEMENT Karine (1,2,3) (1) ICAN, Institut de Cardiometabolisme et nutrition (2) INSERM, UMR1166 (3) University Pierre et Marie Curie-Paris 6 (corresponding author : karine.clement@psl.aphp.fr) Keywords : obesity, microbiota, cardiometabolism Composed of about 10 trillion cells, the human body is host to 100 trillion bacteria which constitute an extremely rich and diverse flora. From a genetic point of view there is 500,000 bacterial genes on average compared to 23,000 genes in the human genome. Indeed, a human being is the result of a mutualistic association, stemming from a co-evolution, whom balance is essential to maintaining the health and well-being. The intestinal flora is now seen as a full organ linking (external) environmental factors and biology of the organism (the host). It provides essential functions throughout life. An imbalance of the intestinal flora or dysbiosis has been demonstrated in a variety of human diseases, whether metabolic, cardiovascular or immuno-inflammatory. These observations have been made in particular through the development, in recent years, of tools for the study of the metagenome allowing the sequencing of bacterial genes from the gut microbiome. A factor very frequently found is the loss of bacterial diversity. Although the loss of diversity is typically associated with taking antibiotics, it is also found in other diseases such as cystic fibrosis, intestinal disorders, and more recently in metabolic diseases such as diabetes and obesity. Recently, our team has helped to show that obese people with a loss of bacterial diversity had more risk factors (dyslipidemia, low-grade inflammation) and improved less these risk factors with a restrictive but rich in fibers diet. This presentation will review the recent discoveries in the field by taking the example of metabolic diseases.

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Signalife Keynote : Emmanuel Van Obberghen

Regulation of insulin action and secretion by microRNAs : relevance for diabetes VAN OBBERGHEN Emmanuel (1,2,3,4) ,DUMORTIER Olivier (1,2,3), HINAULT Charlotte (1,2,3,4), CASAMENTO VIirginie (1,2,3), GAUTIER Nadine(1,2,3) (1) INSERM, U1081, Institute for Research on Cancer and Aging of Nice (IRCAN), « Aging and Diabetes» team, Nice, France (2) CNRS, UMR7284, IRCAN, Nice, France (3) University of Nice-Sophia Antipolis, Nice, France (4 )Clinical Chemistry Laboratory, University Hospital, Nice, France (corresponding author : vanobbeg@unice.fr) Keywords : insulin action, insulin secretion , diabetes, microRNAs, fetal programming The occurrence of type 2 diabetes (T2D) increases at a frightening pace worldwide and is now a major health problem causing an enormous socio-economic burden. Originally genetic factors were suspected in its pathogenesis but the identified genetic variants account for only 10-15% of cases. It is therefore believed that changes in the environment including lifestyle and obesity play a determining role in the rising T2D prevalence. In fact, an emerging paradigm suggests the existence of a complex interplay between genetics, epigenetics and environment. While sedentary lifestyle and overfeeding undoubtedly contribute to the T2D pandemic, the intrauterine fetal environment is an additional influential actor in long-term health and its perturbation predisposes to metabolic diseases such as T2D at adult age.T2D results from 2 defects, insulin resistance coupled to insufficient insulin secretion. Both insulin release and action are regulated by complex signaling pathways, which are fine-tuned to maintain organismal homeostasis. We revealed several mechanisms which can perturb insulin signaling such as serine phosphorylation of the IRS docking proteins induced by lipid peroxidation products and toxic aldehydes, and a negative feedback involving Socs proteins. MicroRNAs are now considered as major players in numerous biological processes, including development and metabolism in all animal species. We were among the first to demonstrate their involvement in insulin secretion and action. For instance we showed that miR-124a targets Foxa2, which regulates the expression of PDX1 and the potassium channel subunits in pancreatic β-cells. Another chief actor in β-cell physiology is miR-375, which we found reduces the protein level of PDK1 of the PI3 kinase cascade and hence decreases glucose effect on growth and insulin gene expression. Notably we revealed miR-375 misexpression in the pancreas of offspring from pregnant rats having suffered from gestational malnutrition. We provide evidence for the role of this aberrant expression in the pancreatic failure of the progeny at adult age. Taking our data in aggregate, we suggest that the fine-tuning of insulin release and action requires the proper expression of several microRNAs and hence their misexpression is likely to contribute to the diabetes pathogenesis. Our work highlights the strong potential of microRNAs in novel approaches for the prevention and treatment of the diabetic disease process.

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Presentation 1: Mathilde Clément

Environmentally selected variants under control of DNA methylation in clonal reproduction Mathilde Clément (1), Aviv Dombrovsky (1,2), Claude Pasquier (3,4), Stephanie Peneaud (5), Neil Ledger (1), Maria Capovilla (1) and Alain Robichon (1) (1) UMR7254 INRA/CNRS/UNS, Institut Sophia Agrobiotech, 400 route des Chappes, BP 167, 06903 Sophia Antipolis, France (2) Volcani Center, Institute of Plant Protection, P.O. Box 6, 50250 Bet Dagan, Israel (3) UMR 6543 du CNRS, Institute of Developmental Biology and Cancer, University Nice Sophia Antipolis, Parc Valrose, 06108 Nice Cedex 2, France (4) University of New Caledonia, PPME, BP R4, F-98851 Noumea, New Caledonia, France (5)Beckman Coulter Genomics SA, 7 parvis Louis Neel, 38040 Grenoble, France (corresponding author : alain.robichon@sophia.inra.fr) Keywords : clonality, epignetic, DNA methylation, phenotypic plasticity The Acyrtosiphon pisum belongs to the Aphididae family, which is characterized by the ability to alternate between sexual and parthenogenetic reproduction modes. This ability accompanied with the new fully sequenced A. pisum genome makes this aphid a good model for epigenetic studies. Epigenetics is a key player in adaptation to environmental changes and regulation of phenotypic plasticity. Selection on asexual A. pisum orange variant towards cold adaptation (8°C) resulted in new A. pisum variant with a unique green pigmentation, a longer life cycle and a heavier weight. Interestingly, these phenotypic changes are heritable in 8°C and reversible when green aphids placed at the normal conditions (22°C). Methylation is a highly conserved epigenetic mark, controlling gene expression leading to environment adaptation. The unchanged genome in clonal individuals prompts us to hypothesize that DNA methylation might orchestrate the phenotypic variability and fitness selection. Thus, we chose to perform the entire methylome and transcriptome analyses on the two A. pisum variants (orange and green). The Gene Ontology (GO) analysis showed that in the cold adapted variant, the genes involved in mRNA catabolic process, DNA- dependent replication, translation process, mRNA splicing and mRNA transport are down regulated. While, the genes involved in metabolism such as aspartate/glutamate metabolism, phosphoinoside metabolism, lipid metabolic process, ATP synthesis coupled to electron transport, mitochondrial electron chain, lipid and carbohydrate transport and GTPase activity are strongly up-regulated. For these differentially expressed genes, the analysis of methylation was carried out separately in the body of the genes and in their promoters. Interestingly, the study demonstrated that a higher methylation rates is correlated with lower expression levels and that a down-regulation of expression is correlated with a higher level of expression. Data suggest that the variable assortments of heavily methylated DNA sites result in phenotypically distinct clonal progenies. In a last experiment, injection of crude extracts from the green variant into the abdomen of the orange variant resulted in green offspring fully adapted to the cold environment. These results led to the assumption that some soluble components, together with methylation and gene silencing are responsible for the aphid adaptation to cold environment.

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Presentation 2: Anne-Laure Hafner

Signalling pathways regulating the generation of brown and white adipocyte progenitors during human embryonic development in vitro HAFNER Anne-Laure (1), MOHSEN-KANSON Tala (1), VILLAGEOIS Phi (1), WDZIEKONSKI Brigitte (1), DANI Christian (1) (1) iBV, UMR CNRS/INSERM, Université Nice Sophia Antipolis, France. (corresponding author : dani@unice.fr) Keywords : adipocyte progenitor, acid retinoic, TGFb, human pluripotent stem cells Brown and white adipose tissues coexist in mammals. Both are involved in the energy balance but have opposite functions: whereas white adipose tissue (WAT) is mainly involved in energy storage, brown adipose tissue (BAT) is specialized in energy expenditure. Although BAT is mainly present in newborns and decreases with aging in humans, metabolically active BAT exists in adults and contributes to the energy balance. Therefore, identification of pathways regulating brown and white adipocyte development in humans is of fundamental importance and could ultimately be clinically applicable. However, nothing is known on the events regulating adipocyte progenitor (AP) generation in humans due to the lack of cellular model. The potential of pluripotent stem cells (induced pluripotent stem cells (iPSCs), and embryonic stem cells), to generate adipocytes has dramatically enhanced the prospects for investigating the earliest steps of adipogenesis during human embryonic development. We have recently reported that brown and white APs generation is regulated by retinoic acid and TGFb pathways during in vitro development of human pluripotent stem cells 1. APs of both phenotypes were derived from hiPScs cultures and their molecular characterization revealed that Pax3 marked brown-like APs. Functional experiments indicated that Pax3 transcription factor was a critical player of human AP fate as its ectopic expression led to reprogram white APs into brown-like APs. The molecular mechanisms mediating Pax3 effects are under investigation. hiPSc differentiated cultures are composed of a complex mix of different cell types, as expected for the development of pluripotent stem cells. Interestingly, we and others observed that APs displayed a weak differentiation potential when isolated from other cell types, strongly suggesting that hiPS microenvironment was required to promote adipogenesis. To test this hypothesis, hiPSc-APs were induced to undergo differentiation in the presence of hiPS-conditioned media. Preliminary experiments showed that soluble factors, which dramatically enhance the potential of APs to undergo differentiation, were secreted during hiPSc development. The findings of the present study could lead to characterize the human AP niche and to new anti-obesity therapies based on the recruitment of APs. 1. Differentiation of human induced pluripotent stem cells into brown and white adipocytes: Role of Pax3. Mohsen-Kanson, T. et al. (2013) Stem Cells Dec

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Session III, Axis 3 Stress Signaling

Chair : T. Magnaldo

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Invited Keynote Lecture : Thomas Lahaye

TAL effectors and TALEN: from microbial corruption to therapy LAHAYE Thomas University of Tübingen, General Genetics, Tübingen, Germany (corresponding author : Thomas.lahaye@zmbp.uni-tuebingen.de) Keywords : Transcription Activator Like Effector (TALE), Gene Editing, Plant Pathology Transcription Activator-Like Effector (TALE) proteins are injected by plant pathogenic bacterial parasites of the genus Xanthomonas into plant host cells to promote bacterial disease. The TALEs DNA binding domain is composed of a variable number of near-identical 33-35 amino acid repeats that differ predominantly in repeat position 12 and 13, the so called repeat variable diresidue (RVD). Each repeat binds a single DNA base and the amino acids occupying the RVD determine base specificity. The simple modular design allows generation of TALE-based DNA binding domains that target any desired DNA target sequence. By now a huge variety TALE fusion proteins have been established mediating targeted modifications to transcriptome, genome and, recently, epigenome. Recent progress on TALE and TALE fusion proteins will be presented.

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Signalife Keynote : Laetitia Perfus-Barbeoch

Genetics and epigenetics in plant-nematode interactions PERFUS-BARBEOCH Laetitia, PRATX Loris, CASTAGNONE-SERENO Philippe, DANCHIN Etienne G.J. and ABAD Pierre INRA, UMR 1355 ISA, CNRS, UMR 7254 ISA, Université de Nice Sophia-Antipolis, UMR ISA, Institut Sophia Agrobiotech, Sophia-Antipolis, France. (corresponding author : zurletto@sophia.inra.fr) Keywords : Plant parasitic nematodes, Comparative genomics, Apomixis, Adaptive evolution, Epigenome Plant parasitic nematodes establish sophisticated relationships with their hosts, essentials for the completion of their parasite life-cycle but dramatically decreasing plant productivity (Quentin et al., 2013). The complete genome sequence of the asexual species Meloidogyne incognita revealed that the assembled sequence consists of homologous but divergent segment pairs that might represent former alleles in this species (Abad et al. 2008). Based on comparative genomics, we identified in this species a set genes preserved during the evolution and of plant-parasitic nematodes only shared with organisms having a plant parasitic lifestyle. These genes represent new targets allowing to develop new methods to control plant-parasitic nematodes but harmless for the environment and the consumer health (Danchin et al, 2013). Another interesting feature of the M. incognita species is the paradox between its apomictic mode of reproduction and its potential host range encompassing more than 3,000 plant species (Castagnone-Sereno et al., 2013). The adaptation of M. incognita to its environment (e.g., reproduction on resistant hosts) raises questions about genome plasticity leading to genetic variation and adaptive evolution. Opportunities for future research on Meloidogyne spp., and more especially the role of the epigenome in the generation of developmental plasticity and virulence in response to environmental stimuli, will be discussed. Abad et al. (2008). Genome sequence of the metazoan plant-parasitic nematode Meloidogyne incognita. Nat Biotechnol. 26(8):909-15. Castagnone-Sereno et al. (2013). Diversity and evolution of root-knot nematodes, genus Meloidogyne: new insights from the genomic era. Annu Rev Phytopathol. 51:203-20. Danchin et al. (2013). Identification of novel target genes for safer and more specific control of root-knot nematodes from a pan-genome mining. PLoS Pathog. 9(10):e1003745. Quentin et al. (2013). Plant parasitic nematode effectors target host defense and nuclear functions to establish feeding cells. Front Plant Sci. 13;4:53.

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Presentation 1: Johanna Chiche

GAPDH controls CD20 expression via NF-kB/HIF-1a and the therapeutic response of DLBCL patients to anti-CD20 therapy CHICHE Johanna (1,2), POMMIER Sebastien (1,3), IMBERT Veronique (2,4), GONCALVES Diogo (2,5), MONDRAGON Laura (1,2), MARCHETTI Sandrine (2,5), GUYOT Mélanie (2,6), PAGES Gilles (2,6), BRIERE Josette (7), PAQUET Agnes (8,9), THIEBLEMONT Catherine (7), and RICCI Jean-Ehrland (1,2) (1) Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe “contrôle métabolique des morts cellulaires”, Nice, France. (2) Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France. (3) Centre Hospitalier Universitaire de Nice, Département d’Anesthésie Réanimation, Nice, France. (4) Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe “inflammation, cancer et cellules souches cancéreuses”, Nice, France. (5) Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe “mort cellulaire, différenciation et cancer”, Nice, France. (6) Institute for Research on Cancer and Aging, CNRS UMR 7284/U INSERM 1081, Centre A. Lacassagne, Nice, France. (7) AP-HP-Hôpital Saint-Louis, Service d’hémato-Oncologie, Université Paris Diderot, Sorbonne Paris Cité, INSERM, UMR 1126, F-75010 Paris, France. (8) CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, France. (9) Université Nice Sophia Antipolis, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, France (corresponding author : chiche@unice.fr) Keywords : glyceraldehyde-3-phosphate dehydrogenase (GAPDH), hypoxia, vascularization, B lymphoma, anti-CD20 therapy Despite their functions in metabolism, the role of glycolytic enzymes in cancer remains elusive. Here, we show that glyceraldehyde-3-phosphate dehydrogenase (GAPDH), but not other tested glycolytic enzymes, increases lymphoma aggressiveness and vascularization. Mechanistically, GAPDH activates NF-kB via its binding to TNF-receptor-associated factor-2 (TRAF2), resulting in an increase in hif-1a transcription and HIF-1 activity. Among the diffuse large B cell lymphoma (DLBCL) biospies from patients, those displaying high levels of GAPDH correlate with a better outcome upon rituximab treatment as a result of an increase in CD20 expression. Thus, GAPDH participates in a positive feedback loop that promotes NF-kB/HIF-1 activation, which favors CD20 expression and may therefore represent a favorable prognosis factor for some DLBCL patients treated with anti-CD20 therapy.

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Presentation 2: Carolina W Ribeiro

Plant Thioredoxins s are involved in the bacterial reception during the nitrogen fixing symbiosis RIBEIRO Carolina W (1), CRESP Fabien Baldacci (1), LAMBERT Annie (1), PIERRE Olivier (1), ALLOING Geneviève (1), BONCOMPAGNI Eric (1), MONTRICHARD Françoise (2), FRENDO Pierre (1) (1) Institut Sophia Agrobiotech – INRA - Sophia Antipolis Cedex – France (2) Institut de Recherche en Horticulture et Semences - Angers Cedex 01 - France (corresponding author : frendo@unice.fr) Keywords : nitrogen fixing symbiosis, redox regulation, thioredoxin, defensis, bacterial differentiation Plants usually interact with soil microorganisms able to contribute to the absorption of nutrients. In this context, leguminous plants associated with soil nitrogen-fixing bacteria develop root nodules in which atmospheric nitrogen (N2) is reduced to ammonium used by host plant. In root nodules, the bacteria differentiate in nitrogen-fixing bacteroids which are able to reduce N2. The cellular redox state of both partners regulates this plant-microbe interaction. Amongst the proteins involved in the regulation of redox state, Thioredoxins (Trx) play key roles in the redox regulation of target proteins through the reduction of disulfur bridges. We have isolated and characterized four members of a Trx family specifically expressed during the nitrogen-fixing symbiosis in the model plant Medicago truncatula and thus called Trx s. Spatiotemporal analysis of Trx s gene expression pattern using promoter::reporter gene showed that these genes are expressed in the infection zone of the nodule. Analysis of the cellular localisation of the Trx s using Trx::GFP fusion localisation and immunolocalisation showed that plant Trx s are targetted to the symbiosome, the nitrogen-fixing organelle containing the bacteroids. Silencing of Trx s using RNAi constructs reduces the nitrogen fixation efficiency of the plants without altering the root nodule formation showing that Trx s plays a key role in the symbiosis regulation. To define the protein targets of the Trx s, we tested the nodule cysteine rich (NCR) peptides as substrate of the Trx s. NCR peptides are plant defensin-like peptides targeted to bacteroids, and are involved in their differentiation to nitrogen-fixing bacteroids. Our preliminary results showed that Trx s1 is able to reduce NCR peptides in vitro and in vivo. In conclusion, our results indicate that the plant modifies the redox state of defensin-like peptides involved in bacteria differentiation via a post-translational modification of disulfide bonds with sp! ecific t hioredoxins. Interestingly, such regulation has been observed in the animal kingdom during symbiotic interactions in insects or defense mechanisms in human. This work is supported by Conselho Nacional do Desenvolvimento Científico e Tecnológico (CNPq – Brasil)

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Session IV, Axis 4 Signaling in aging and disease Progression

Chair : J-F. Tanti

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Invited Keynote Lecture : Patrick Mehlen

The dependence receptor notion: from a cell biology paradigm to alternative anti-cancer therapies. MEHLEN Patrick CRCL, UMR INSERM 1052, CNRS 5286, Centre Léon Berard, 28 Rue Laennec, 69008 LYON (corresponding author : patrick.mehlen@lyon.unicancer.fr) Keywords : Cancer, dependence receptor, apoptosis, embryonic development, tumor suppressor gene A few years ago, an original concept of cell biology was proposed: whereas the classic dogma postulates that transmembrane receptors are inactive unless bound by their specific ligand, it was suggested that some receptors may be active not only in the presence of their ligand, but also in their absence. In this latter case, the signaling downstream of these unbound receptors leads to apoptosis. These receptors were consequently named “dependence receptors”, as their cell expression renders the cell’s survival dependent on the presence in the cell environment of its respective ligand. This dual function is hypothesized to lead these receptors to have key roles both during embryonic development and in the regulation of tumorigenesis. In the context of cancer, the hypothesis is that these receptors are tumor suppressors that would limit tumor progression by inducing apoptosis of tumor cells outside of settings of ligand accessibility/availability. This was recently formally demonstrated for the prototypical dependence receptors that bind netrin-1 –i.e., DCC and UNC5H-. Because expression of DCC and UNC5H is a constraint for tumor progression, their expression is often lost in many aggressive cancers. However, a loss of dependence receptors is not always the selective advantage used by tumor cells to escape this survival dependence on the presence of the ligand. Indeed, it was showed that in many cancers such as metastatic breast cancer, lung cancer or neuroblastoma, tumor cells acquire the preferred autocrine expression of netrin-1. This selective advantage for the tumor is much more appealing in terms of therapeutic strategy. Indeed, the titration of the ligand by a molecule that interferes on the interaction between a dependence receptor and its ligand should lead to tumor cell death. Along this line, it was shown that titration of netrin-1 by a drug candidate allows tumor cell death in vitro and triggers regression of tumors and metastases in mice. Of interest, this gain of ligand is probably not limited to netrin-1 but may possibly be extended to the other ligands of other dependence receptors. Thus, drugs based on the interference on the interaction between dependence receptors and their ligands are under development. The first human trial using an agent interfering between netrin-1 and its receptors should begin in mid-2015. Thus, from a basic cell biology concept, our laboratory may, within the next few years, provide new tools to fight against cancer

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Signalife Keynote : Pierre Leopold

Studying growth control in flies: from developmental regulations to neoplasms ANDERSEN Ditte, COLOMBANI Julien, LEOPOLD Pierre IBV, Nice, France (corresponding author : leopold@unice.fr) Keywords : Growth control, insulin/IGF, nutrition, tumor development, Drosophila Animal growth is a complex process that is intimately linked to the developmental program in order to form adults with proper size and proportions. This is achieved through the action of intrinsic (tissue-autonomous) programs, combined to hormonal regulations that convey information from the environment. The fruit fly has emerged as a model of choice to study both types of controls. Our work recently addressed the question of the coordination between tissue growth and developmental timing. Indeed, tissue-autonomous growth feeds back on the time of development, so that the juvenile growth period arrests when all tissues have reached their target size. In a genetic screen aimed at identifying molecules involved in such feedback, we have isolated Dilp8 as a hormone produced by growing or regenerating tissues that prevents the transition from juvenile to adult. In the same screen, we also identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour-necrosis factor receptor (TNFR) superfamily. We show that Grnd mediates both pro-apoptotic and metastatic functions of Eiger (Egr), the unique Drosophila TNF. We also uncover a distinct function for Grnd in linking polarity defects with neoplastic growth: Grnd localises to the sub-apical membrane domain with the cell polarity determinant Crumbs and physically interacts with components of the Crb complex. This interaction allows Grnd to couple Crumbs-induced loss of polarity with JNK activation and neoplastic growth. Therefore, Grnd represents the first example of a TNF receptor that integrates signals from both Egr/TNF and apical polarity determinants to induce JNK-dependent cell death or growth and proliferation.

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Presentation 1: Franck Ceppo

Implication of the inflammatory kinase Tpl2 in cytokine- and macrophage-induced insulin resistance CEPPO Franck (1), BERTHOU Flavien (1), JAGER Jennifer (1), DUMAS Karine (1), TRAN Albert (2), VIDAL Hubert (3), GUAL Philipe (2), CORMONT Mireille (1), TANTI Jean-François (1) (1) Inserm, UMR 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 7, Faculté de Médecine, Univ Nice Sophia Antipolis, Nice, France. (2) Inserm, UMR 1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 8, Faculté de Médecine, Univ Nice Sophia Antipolis, Nice, France. (3) INSERM U1060, Cardiology, Metabolism and Nutrition Laboratory (CarMen), Univ Lyon 1, Lyon, France. (corresponding author : Franck.Ceppo@unice.fr ) Keywords : Insulin signaling, obesity, diabetes, adipose tissue, inflammation Obese adipose tissue (AT) is infiltrated by macrophages and a cross-talk between macrophages and adipocytes involving bacteria lipopolysaccharides (LPS), fatty acids and cytokines contributes to AT inflammation and dysfunction that participate in insulin resistance. However, the inflammatory signaling proteins underlying this cross-talk remain to be identified. The MAP kinase kinase kinase Tpl2 (Tumor progression locus 2) is activated by several inflammatory stimuli including LPS and its expression is deregulated in several inflammatory diseases. Thus, we hypothesized that Tpl2 could be an attractive candidate involved in adipocyte/macrophage cross-talk in obese AT. We found Tpl2 mRNA up-regulated in AT of obese mice and patients. In AT of obese mice, Tpl2 expression is increased both in adipocytes and in pro-inflammatory macrophage fraction. In adipocytes, inflammatory cytokines increased Tpl2 expression through the IKKbeta/NFkB pathway and Tpl2 inhibition prevented the lipolysis and the down-regulation of insulin signaling induced by cytokines. We then used a co-culture system and conditioned medium (CM) from macrophages to assess the implication of Tpl2 in the cross-talk between adipocytes and macrophages. Pharmacological inhibition of Tpl2 in the co-culture markedly reduced lipolysis and cytokine production and prevented the decrease in adipocyte insulin signaling. Tpl2 knock-down in co-cultured adipocytes reduced lipolysis but had a weak effect on cytokine production and did not prevent the alteration of insulin signaling. Also, Tpl2 silencing in adipocytes did not prevent the deleterious effects of CM from LPS-activated macrophages. By contrast, Tpl2 silencing in co-cultured macrophages resulted in a marked inhibition of cytokine production and prevented the alteration of adipocyte insulin signaling. Furthermore, when Tpl2 was inhibited in LPS-activated macrophages, the produced CM did not alter adipocyte insulin signaling and did not induce an inflammatory response in adipocytes. These data establish that Tpl2 is implicated in deleterious effects of cytokines on adipocytes functions, Tpl2, mainly in macrophages, is involved in the cross-talk between adipocytes and macrophages that promotes inflammatory changes and alteration of insulin signaling in adipocytes. The deregulated expression of Tpl2 in adipose tissue suggests that Tpl2 may be a new actor in adipose tissue dysfunction in obesity.

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Presentation 2: Julien Cherfils-Vicini

TRF2 inhibits a cell-extrinsic pathway through which natural killer cells eliminate cancer cells CHERFILS-VICINI Julien (1), BIROCCIO Annamaria (2), AUGEREAU Adeline (1), PINTE Sébastien (3), JAMET Karine (1), CERVERA Ludovic (1), PEEPER Daniel (4), COGNET Céline (5), SMYTH Mark J. (6), VIVIER Eric (5), GILSON Eric (1) (1) Institute for Research on Cancer and Aging, Nice (IRCAN), Nice University, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice 06107, France. (2) Regina Elena National Cancer Institute, Rome 00158, Italy. (3) Biology Instituteof Lille, CNRS UMR8161, Pasteur Institute of Lille, BP 447, 59021, LILLE cedex, France (4 )Division of MolecularGenetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands (5) Centre d’Immunologiede Marseille-Luminy, Aix-Marseille Université, UM2 INSERM UMR1104, CNRS UMR7280, Marseille 13288, France and Hôpital de la Conception, Assistance Publique–Hôpitaux de Marseille, Marseille 13005, France. (6) Cancer Immunology Program, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, 3002 Victoria,Australia. (corresponding author : julien.cherfils@unice.fr) Keywords : Telomeres, TRF2, Natural Killer cells, Cancer, interstitial telomeric sequences Telomeres, the most distal structures of chromosomes, play an important role in genome stability and dysfunctions of these structures activate a cell-intrinsic program that leads to senescence, cell cycle arrest or apoptosis. Telomeres protect chromosome extremities from being repaired and recognized as accidental double strand DNA breaks. For instance, loss of TRF2, a major telomere protein in mammals, triggers an ATM-dependent DNA Damage Response (DDR) leading to growth arrest, senescence or apoptosis. This mechanism is considered as an intrinsic barrier to tumor development. As we observed that TRF2 is often upregulated in human cancer samples and that in a Ras V12 contexture, TRF2 modulation do not impact neither tumor cell proliferation nor clonogenicity in vitro, we address the question of a possible link between TRF2 dosage and cancer immunity. We demonstrate for the first time that this TRF2 overexpression in tumor cells decreased their ability to recruit and activate Natural Killer Cells, leading to an increase of the tumor growth and a decrease to the overall survival. Reciprocally, a decreased expression of TRF2 enables tumor cells to be more easily eliminated by NK cells and thus decreased tumor growth and increased overall survival. Moreover, in vitro coculture assay show that the TRF2 overexpression inhibits NK cell degranulation. In addition, the depletion of NK cells thanks to NK1.1 antibody restore the tumorigenicity of TRF2 deficient cells, showing that TRF2 is required to bypass NK cell immunosurveillance. Thanks to in vitro and in vivo studies, we were able to show that TRF2 can bind DNA outside telomeres, on Interstitial Telomeric Sequences (ITS). This extra-telomeric binding of TRF2 leads to gene modulation. Among the genes that are modulated by TRF2, we showed that the Heparan Sulfate 3-O-sulfotransferase 4 (HS3ST4), an enzyme implicated in the sulfation of cell surface glycoproteins, is positively modulated by the overexpression of TRF2 and inhibited NK cells recruitment in an epistatic relationship with TRF2. Consistently with this mechanism, we observed a progressive up-regulation of TRF2 that correlated with a progressive decreased in NK cell infiltration during the early development of human colon cancer. These results reveal, both in mouse models and human colon cancer samples, a totally new TRF2-dependent pathway that is tumor-cell extrinsic and regulates NK cell immunity via at least by the sulfation of proteoglycans.

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Session V, Axis 5 New principles in signaling and applications

Chair : F. Besse

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Invited Keynote Lecture : Klaus Hahn

Engineering proteins to control GTPase circuits in living cell HAHN Klaus Michael Department of Pharmacology, Director, UNC-Olympus Imaging Center, Genetic Medicine Building CB7365, UNC Chapel Hill, Chapel Hill, NC 27599-7365, USA (corresponding author : khahn@med.unc.edu) Keywords : optogenetics, biosensors, allosterism, imaging, motility The spatio-temporal dynamics of signaling determines how specific proteins can produce a host of different, sometimes opposing responses. This talk will describe approaches to visualize and manipulate signaling networks in living cells and animals, including broadly applicable methods to control proteins with light (LOVTRAP). The role of Rho family GTPase “circuits’ in regulating motility will be probed using engineered allosteric switches to control the activity and interactions of kinases (uniRapR and RapRTAP). New biosensors for Rho family molecules, some based on novel designs, play an important role in these studies.

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Signalife Keynote : Franck Delaunay

Coupling between the circadian clock and cell cycle oscillators The ERASySBio+ Circadian Clock and Cell Cycle Systems in Cancer Project Consortium Université Nice Sophia Antipolis, CNRS, INSERM, Institut de Biologie Valrose, Nice, France Systems Biology Centre, University of Warwick, Coventry, CV4 7AL, UK Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands INSERM, UMRS776 "Rythmes biologiques et cancers", Paul Brousse Hospital, Villejuif, France (corresponding author : delaunay@unice.fr) Keywords : Circadian clock, Cell cycle, Coupled oscillators, Phase-locking Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression and hence its biological relevance is not understood. In particular, we do not know how the temporal organisation of cell division at the single cell level produces this daily rhythm at the tissue level. Combination of multispectral imaging of single live cells, computational methods and mathematical modelling allows us to reconstruct the joint phase trajectory of the clock and cell cycle and thus directly probe their temporal coordination. Using this system biology approach, we show that in unperturbed mouse fibroblasts, the cell cycle and circadian clock robustly phase-lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators have a fixed relative phase and oscillate with a common frequency. Dexamethasone-induced synchronisation reveals an additional clock state: as well as the low-period phase-locked state there is a coexisting state with a ~24h period clock and a faster cell cycle. Data also suggest that the cell cycle can control the clock and entrain its period thus contributing to a bidirectional coupling. These results collectively provide a comprehensive model for the intracellular coupling between two key biological oscillators. The temporal coordination of cell division by phase-locking to the clock at a single cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases including cancer.

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Presentation 1: Benjamin Mauroy

An archetypal mechanism for branching organogenesis. CLEMENT Raphaël (1,2), MAUROY Benjamin (2) (1) Laboratoire JA Dieudonné, Université de Nice-Sophia Antipolis, France. (2) Institut de Biologie du Développement de Marseille, Université de Marseille, France. (corresponding author : mauroy@unice.fr) Keywords : morphogenesis, organogenesis, branching, lung, physical instability Branched structures are ubiquitous in nature, both in living and non-living systems. While the functional benefits of branching organogenesis are straightforward, the developmental mechanisms leading to the repeated branching of epithelia in surrounding mesoderm remain unclear. Both molecular and physical aspects of growth control seem to play a critical role in shape emergence and maintenance: on the molecular side, the existence of a gradient of growth-promoting ligand between epithelial tips and distal mesenchyme seems to be common to branched organs. On the physical side, the branching process seems to require a mechanism of real-time adaptation to local geometry, as suggested by the self-avoiding nature of branching events. In this paper, we investigate the outcomes of a general 3D growth model, in which epithelial growth is implemented as a function of ligand income, while the mesenchyme is considered as a proliferating viscous medium. Our results suggest that the existence of a gradient of growth-promoting ligand between distal and proximal mesenchyme implies a growth instability of the epithelial sheet, resulting in spontaneous self-avoiding branching morphogenesis. While the general nature of the model obviously prevents from fitting the development of a specific organ, it suggests that few ingredients are actually required to achieve branching organogenesis. The authors thank Stephane Douady for his contributions to this work; Pierre Blanc and Vincent Sapin for early discussions about lung development; Erwan Poindron for movies designing. This work has been supported by the program ”Aide aux jeunes chercheurs” of the city of Nice; and by the CNRS program PEPS PTI. 1. An archetypal mechanism for branching organogenesis, R. Clément and B. Mauroy, Phys. Biol. 11 016003, 2014. 2. Branching geometry induced by lung self-regulated growth, R. Clément, S. Douady* and B. Mauroy*, Phys. Biol. 9, 066006 (9pp), 2012 (* These authors contributed equally to this work). 3. Shape self-regulation in lung morphogenesis, R. Clément, P. Blanc, B. Mauroy, V. Sapin and S. Douady. PLoS ONE 7(5): e36925, 2012.

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Presentation 2: Rihab Loudhaief

Oral intoxications by low charge of non-pathogenic bacteria generate transient Enterocyte-dependent dysplasia in the Drosophila midgut Loudhaief Rihab, Benguettat Olivia, Brun-Barale Alexandra, Esposito Marie-Paule, Amichot Marcel and Gallet Armel Institut Sophia Agrobiotech, Alpes maritimes, Nice, France (corresponding author : Armel.GALLET@unice.fr) Keywords : intestinal homeostasis, infection with low charge of bacteria, Dysplasia, stress signaling pathways, Recovery The digestive tract is facing daily various ingested microbes and substances. The gut homeostasis is responsible of the maintenance of the gut integrity by renewing damaged or dead cells. Pathogenesis can arise from an imbalanced interaction between the host and the ingested microbes. Recently Drosophila melanogaster has emerged as a valuable tool for modeling the host-pathogen interactions in the digestive tract. Besides, there is a remarkable conservation of bacterial pathogenesis and of host defense mechanisms between vertebrates and Drosophila. Nevertheless, these studies were carried out with high concentrations of bacteria (ranging from 108 to 109 CFU/fly), above the doses usually ingested during the life. Therefore to decipher how the gut homeostasis adapts to environmental challenges, we designed experiments mimicking the ingestion of low doses of exogenous bacteria (104 CFU/fly). First, we choose the non pathogenic Gram+ bacterium Bacillus thuringiensis (Bt), that is widely used as bioinsecticides. Then, we have used the opportunistic Gram- bacterium Escherichia coli. In this presentation, I will describe how the ingestion of a low charge of bacteria induces a moderate stem cell proliferation leading to a 30% increase of enterocyte number. Moreover I did not observe the usual enterocyte death associated with a huge charge of bacteria. Instead, the elevated number of enterocytes gives rise to a transient intestinal dysplasia that is recovered five days post-intoxication. Finally I will show you how the two signaling pathways JNK and Hippo may cooperate to maintain the equilibrium between cell survival and cell death to adjust the cell number to the organ size.

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POSTERS Wine and Cheese Poster Session

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Poster Session I, Axis 1 Cellular Architecture of Signaling Pathways

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BOULAKIRBA Sonia 1.1

The Arf6 Exchange Factor EFA6 and endophilin directly interact at the plasma membrane to control clathrin-mediated endocytosis BOULAKIRBA Sonia (1), MACIA Eric (1), PARTISANI Mariagrazia (1), LACAS-GERVAIS Sandra (2), BRAU Frédéric (1), LUTON Frédéric (1), FRANCO Michel (1) (1) Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275 CNRS-Université de Nice Sophia-Antipolis, Valbonne France (2) Centre Commun de Microscopie Appliquée, Université de Nice Sophia-Antipolis, Nice France (corresponding author : franco@ipmc.cnrs.fr) Keywords : ArfGEF, N-BAR domain, membrane curvature, endocytosis Members of the Arf family of small G proteins are involved in membrane traffic and organelle structure. They control the recruitment of coat proteins, and modulate the structure of actin filaments and the lipid composition of membranes. The Arf6 isoform and its specific exchange factor EFA6 are known to regulate the endocytic pathway of many different receptors. In order to determine the molecular mechanism of the EFA6/Arf6 function in vesicular transport we searched for new EFA6 partners. In a two hybrid screening using the catalytic Sec7 domain as a bait, we identified endophilin as a new partner of EFA6. Endophilin contains an N-Bar domain responsible for membrane bending and an SH3 domain responsible for the recruitment of dynamin and synaptojanin, two proteins involved respectively in fission and uncoating of clathrin-coated vesicles. Using purified proteins, we confirmed the direct interaction, and identified the N-Bar domain as the binding motif to EFA6. We showed that endophilin stimulates the catalytic activity of EFA6 on Arf6. In addition, we observed that the Sec7 domain competes with flat but not with highly curved lipid membranes to bind the N-Bar. In cells, expression of EFA6 recruits endophilin to EFA6-positive plasma membrane ruffles, while expression of endophilin rescues the EFA6-mediated inhibition of transferrin internalization. Overall, our results support a model whereby EFA6 recruits endophilin on flat areas of the plasma membrane to control Arf6 activation and clathrin-mediated endocytosis.

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BOULTER Etienne 1.2

Regulation of rigidity sensing and integrin-dependent mechanotransduction by CD98hc (SLC3A2) BOULTER Etienne (1), ESTRACH Soline (1), FERAL Chloé (1) (1) Institute for Research on Cancer and Aging, Nice, University of Nice Sophia-Antipolis, Institut National de la Santé et de la Recherche Médicale U1081, Centre National de la Recherche Scientifique UMR 7284, Centre Antoine Lacassagne, Nice 06107, France. (corresponding author : boulter@unice.fr) Keywords : Integrins, Mechanotransduction, RhoA, Dermis, Membrane microdomain In living organisms, cells continuously probe and evaluate the mechanical properties of their surrounding microenvironment. In return, the mechanical signals issued by the environment generate signaling in cells known as mechanotransduction, which affect their behavior and fate. A large part of this mechanosensing process occurs at the level of cell-matrix adhesion structures which comprise integrin receptors indirectly linked to the actin cytoskeleton via an intracellular complex. While it has long been known that integrins sense and transmit forces from the ECM to the intracellular adhesion complex, it is still unclear how the various other transmembrane proteins present in adhesion complexes may affect mechanotransduction and force sensing. Here, we show that CD98hc (SLC3A2), an aminoacid transporter and integrin coreceptor that does not bind the ECM, is required for cells to evaluate the rigidity of their environment and generate proper mechanotransduction signals. Using fibronectin-coated (FN) magnetic beads and polyacrylamide hydrogels, we show that loss of CD98hc results in impaired RhoA activation and YAP/TAZ transcriptional activity. Mechanistically, we demonstrate that the loss of RhoA activation in response to force applied on integrins is due to a defect of activation of the RhoA-specific RhoGEFs, LARG and GEF-H1 which become constitutively localized at the cell membrane upon loss of CD98hc. We also show that mechanotransduction triggered by force application on integrins requires intact cholesterol-enriched membrane microdomains which properties and behavior are affected by the loss of CD98hc. Using traction force mapping on FN-coated hydrogels, we determined that CD98hc-depleted fibroblasts fail to generate contractile forces upon stiffening of the hydrogel. Finally, we show that, in vivo, specific depletion of CD98hc in mouse dermal fibroblasts by homologous recombination (CD98hcfl/fl, fsp1 CRE::ER) results in a decreased rigidity of the de! rmis bec ause of an abnormal organization of the ECM as well as various defects in skin homeostasis and wound healing. In conclusion, we show that CD98hc, despite not being a primary mechanosensor itself, creates a membrane microdomain-dependent signaling hub required in order to generate mechanotransduction via integrin receptors.

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FOUCHER Kevin 1.3

Keeping telomere under wraps to avoid DNA damage: a job for TRF2 FOUCHER Kevin (1), BENARROCH-POPIVKER Delphine (1), PISANO Sabrina (1), GAY Alexandre (1), MENDEZ-BERMUDEZ Aaron (1), LATRICK Chrysa (1), PEI Bei (1), MIRON Simona (2), LE DU Marie-Hélène (2), GILSON Eric (1) and GIRAUD-PANIS Marie-Josèphe (1) (1) Institute for the Research on Cancer and Aging, UMR 7284 CNRS, U1081 INSERM, Faculté de Médecine, Université de Nice-Sophia Antipolis, Nice, France (2) DSV/IBi Tec-S/SB2SM/LBSR, Commissariat à l'Energie Atomique Saclay, Gif sur Yvette, France (corresponding author : Marie-Josephe.GIRAUD-PANIS@unice.fr) Keywords : Telomeres, TRF2, DNA Topology, DNA Damage Response, Cancer The human shelterin protein TRF2 is capable of condensing DNA in vitro, a property that is thought to be important for telomeres folding and during telomeres replication (Amiard et al, NSMB, 2007, Ye et al, Cell, 2010, Poulet et al, NAR, 2012). Using Atomic Force Microscopy, we have discovered that this topological activity of TRF2 is based on the wrapping of 100bp of DNA around the protein. Protein footprinting performed on the TRF2-DNA complex show that this wrapping involves residues in the homodimerization (TRFH) domain organized as a “DNA path” around this domain. Mutations of several of these residues gave rise to a mutant that we dubbed Top-less since it exhibits a topology activity largely reduced as seen by AFM, topology assays and single strand invasion assays, while it is still capable of binding telomeric DNA. Amazingly, expression of this mutant does not rescue the activation of the DNA damage response triggered at telomeres by TRF2 downregulation. We propose that TRF2-dependent DNA wrapping is necessary for telomere protection against unsuited activation of the DNA damage response.

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GIORDANO Cécile 1.4

Transduction of Hedgehog signal in Drosophila GIORDANO Cécile, THEROND Pascal, RUEL Laurent Institut de Biologie Valrose (iBV), Centre de Biochimie, Nice, France (corresponding author : ruel@unice.fr) Keywords : Signaling, Hedgehog, Cubitus Interruptus, Drosophila Melanogaster, Development Hedgehog (Hh) is a morphogene that controls in a gradient-dependent manner cell growth and differentiation in both invertebrates and vertebrates. As dysfunction in Hh activity or spreading can cause developmental diseases or cancer, it is important to deeply analyse Hh signal transduction pathway. In Drosophila, the Hh signal transduction is initiated by interaction of Hh with its receptor Patched that induces Smoothened (Smo) activation. This leads to signal transmission to a cytoplasmic complex composed of four proteins: the kinase Fused (Fu), the protein kinase A (PKA), the kinesin like Costal2 (Cos2) and the transcription factor Cubitus interruptus (Ci). I analysed the effect of the protein kinase Fu on conformational changes and phosphorylations within the protein complex. I first demonstrated by using Bimolecular Fluorescence Complementation (BiFC) that both the (i) PKA/Ci association within the cytoplasmic complex and (ii) the Hh-mediated disruption of PKA from Ci, are independent of the catalytic activity of Fu, but dependent on Smo. Secondly, I also showed by BiFC and co-immunoprecipitation, that Hh induces the association between Fu and Ci and increases the phosphorylation of Ci by Fu. This regulation induces conformational changes in the transduction complex leading to Ci activation. All together my data revealed conformational changes of two different kinases, PKA and Fu within the protein complex involved in Hh transduction. Depending on Hh signal, PKA and Fu phosphorylate and associate with Ci in order to generate different isoforms and different activities of Ci.

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GIROUD Maude 1.5

Let-7i-5p and miR-125b-3p as potential regulators of the conversion of white into brown adipocytes GIROUD Maude(1), BARQUISSAU Valentin(2), KARBIENER Michael(3), PISANI Didier(1), MAIRAL Aline(2), BERANGER Guillaume(1), BEUZELIN Diane(2), GHANDOUR Rayane(1), CHAMBARD Jean-Claude(1),SCHEIDELER Marcel(3), LANGIN Dominique(2), AMRI Ez-Zoubir(1) (1) CNRS UMR7277 Insitut de Biologie Valrose, Campus Pasteur, Univ Nice Sophia Antipolis, Nice, France (2) INSERM UMR1048, Institute of Metabolic and Cardiovascular Diseases Obesity Research Laboratory, University Paul Sabatier, Toulouse, France. (3) Institute for Genomics and Bioinformatics, RNA Biology Group, Graz University of Technology, Austria. (corresponding author : Ez-Zoubir.AMRI@unice.fr) Keywords : Obesity, Diabetes, hMADS cells, miRNAs, UCP1 Brown Adipose Tissue (BAT) has long been thought to be absent or very scarce in human adults. The recent discovery of thermogenic BAT in human adults opened the field for innovative strategies to combat overweight/obesity and associated diseases such as type 2 diabetes. This energy-dissipating function of BAT is responsible for adaptive thermogenesis in response to cold stimulation. In this context, adipocytes can be converted, within white adipose tissue, into multilocular adipocytes expressing UCP1, named “inducible brown”, “brite” or “beige” adipocytes. We take advantage of our human cellular model (hMADS) to identify and/or validate critical factors involved in the induction of a thermogenic program within adipocytes. Among these factors, we evaluate the role of microRNAs as novel regulators of brown/”brite” adipocyte differentiation and conversion. We carried out a miRNA microarray and identified four miRNAs that were down-regulated upon a prolonged rosiglitazone treatment which leads to britening of hMADS cells. We focused our interest on let-7i-5p and miR-125b-3p. We validated their down regulation in hMADS cells and in differentiated human adipocytes derived from primary cultures of adult donors. Finally the expression of let-7i and miR-125b-3p was also found down-regulated in adipose tissues of cold-exposed and β3-adrenergic receptor agonist (CL316 243) treated mice. Functional studies in hMADS cells demonstrated that over-expression of let-7i results in inhibition of mRNA as well protein UCP1 expression and oxygen consumption. Over-expression of miR-125b-3p decreases the basal oxygen consumption and maximal mitochondrial respiration rate. Injection of the miRNA directly in the BAT and sub-cutaneous adipose tissue of mice treated with CL316 243 leads to a decrease of mRNA UCP1 expression in this tissue. Altogether, our data show that let-7i-5p and miR-125b-3p represent important miRNAs candidates involved in the formation of brite! adipocy tes and potential target to prevent and/or cure overweight and obesity.

42

GORE Tanvi 1.6 A genome-wide RNAi screen to identify new regulators of Hedgehog secretion GORE Tanvi (1), MATUSEK Tamas (1), RALLIS Andrew (1),LAVENANT-STACCINI Laurence (1), THEROND Pascal (1) (1) Institute of Biology Valrose, UNS - CNRS UMR7277 - Inserm U1091 (Corresponding author : therond@unice.fr) Keywords : Hedgehog secretion, Drosophila, RNAi screen, Rab8 Hedgehog is a highly conserved and secreted morphogen which induces different cell fates at short and long ranges. It is known that hedgehog is dually lipidated but is not well understood how this highly hydrophobic protein can spread over many cells. Currently in the literature there are several hypotheses proposed for different trafficking pathways involved in the secretion of Hedgehog. The transporter, dispatched, is the only known protein to be dedicated to hedgehog secretion. To identify novel proteins regulating the secretion of Hedgehog, we developed a genome-wide RNAi screen using the Drosophila as a model. We screened the VDRC KK RNAi transgenic line collection which target most of (80%) the Drosophila genome. We screened for the suppressors of lethality and obtained 80 candidates. I will present our RNAi screening strategy and one of our strong positive hits – Rab8 GTPase. Interfering with Rab8 function in Hh producing cells leads to a subcellular Hh localization change and changes the amount of Hh release. I am currently characterizing and analyzing Rab8 further by looking where Rab8 is acting on Hh. This work is supported by AXA doctoral fellowship.

43

HARB Kawssar 1.7

A novel molecular mechanism specifying a subpopulation of layer V projection neurons in the developing mouse cortex HARB Kawssar, ALFANO Christian, MAGRINELLI Elia, STUDER Michèle iBV, centre de biochimie, Université de Nice-Sophia antipolis, Nice, France (corresponding author : michele.studer@unice.fr) Keywords : cerebral cortex, layer V neurons, transcription facor Ctip2, chromatin remodelling protein Satb2, pons, corpus callosum The mammalian neocortex is organized into six neuronal layers distinguished by their connectivity, molecular code and cytoarchitecture. Each layer is constituted by different neuronal populations; for example, layer V neurons consist of two major types of projection neurons (PNs): corticofugal (subcerebral and corticostriatal) and corticocortical (callosal) PNs. So far, different transcription factors specifying these cell populations have been identified. Among them, Fezf2 and Ctip2 promote the specification of subcerebral PNs, whereas Satb2 promotes callosal identity, mainly by repressing Ctip2 transcription through the recruitment of the NURD complex to the Ctip2 locus. However, a subpopulation of double Satb2/Ctip2-expressing (C/S+) cells still persists in the neocortex, particularly in the primary motor area, but the mechanisms allowing co-expression of these two factors, as well as function and connectivity of C/S+ cells is still unknown. We found that in neocortices lacking COUP-TFI, a transcription factor modulating neocortical areal and cell-type specification, the number of C/S+ cells increases abnormally in layer V of the prospective primary somatosensory area. By biochemical, tracing and electrophysiological approaches we have characterized this population in normal and COUP-TFI mutant cortices and identified the molecular mechanism allowing co-expression of Satb2 and Ctip2 in these cells. Together, our results have unravelled a novel molecular process specifying a new PN sub-population within layer V.

44

MESMIN Bruno 1.8

A pharmacological approach to understand the requirement of OSBP, a cholesterol/PI(4)P exchanger, in cancer cell survival. MESMIN Bruno (1), BIGAY Joëlle (1), LACAS-GERVAIS Sandra (2), DRIN Guillaume (1), ANTONNY Bruno (1) (1) Institut de Pharmacologie Moléculaire et Cellulaire, Université Nice Sophia Antipolis and CNRS, 06560 Valbonne, France. (2) Centre Commun de Microscopie Appliquée, Université Nice Sophia Antipolis, Parc Valrose, 06000 Nice, France. (corresponding author : antonny@ipmc.cnrs.fr) Keywords : OSBP, cholesterol, PI(4)P, ORPphilin, cancer By studying OSBP (Oxysterol binding protein) mechanism of action, we have demonstrated that this protein creates membrane contact sites between ER and trans Golgi and organizes an original lipid exchange that has many pathophysiological implications. OSBP exchanges cholesterol for the phosphoinositide PI(4)P, which is then hydrolyzed and acts as a fuel to make cholesterol transfer irreversible. This study explains how cholesterol is actively transported from the ER to the Golgi in a manner that is self-regulated over time (1). Recently, OSBP has been described to be the specific target a new class of natural compounds with anticancer activity, called “ORPphilins” (2). We are studying the pharmacology of one of these drugs (OSW1) to understand the cancer cell dependence on OSBP. We examine its effects on lipid transport and metabolism controlled by OSBP, as well as on organelle morphology. In particular, we compare the action of OSW1 with that of natural ligands of OSBP known to have no anti-cancer activity. Our work will bring new insights on the mechanism of action of compounds with possible therapeutic role, and will clarify the physiologic role of OSBP. This work is supported by the ERC, the ANR and the Conseil Général des Alpes-Maritimes. (1) Mesmin B, Bigay J, Moser von Filseck J, Lacas-Gervais S, Drin G, Antonny B. A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell. 2013 Nov 7;155(4):830-43 (2) Burgett AW, Poulsen TB, Wangkanont K, Anderson DR, Kikuchi C, Shimada K, Okubo S, Fortner KC, Mimaki Y, Kuroda M, Murphy JP, Schwalb DJ, Petrella EC, Cornella-Taracido I, Schirle M, Tallarico JA, Shair MD. Natural products reveal cancer cell dependence on oxysterol-binding proteins. Nat Chem Biol. 2011 Aug 7;7(9):639-47

45

Poster Session II, Axis 2 Plasticity and Signaling

46

BEN OTHMAN Nouha 2.1

Beta-cell regeneration induction using a chemical compound BEN OTHMAN Nouha, COURTNEY Monica, VIEIRA Andhira, DRUELLE Noémie, AVOLIO Fabio, GJERNES Elisabet, FAURITE Biljana, NAPOLITANO Tiziana and COLLOMBAT Patrick Université de Nice-Sophia Antipolis, FR-06108 Nice, France Inserm U1091, IBV, Diabetes Genetics Team, FR-06108 Nice, France JDRF,26 Broadway, NY-10004, USA (corresponding author : Patrick.COLLOMBAT@unice.fr) Keywords : β-cell regeneration, Endocrine pancreas, Mouse, Diabetes , Pax4 Background and aims: Type 1 diabetes arises as a result of a cell-mediated autoimmune destruction of insulin-producing pancreatic β-cells. One avenue of research for a potential therapeutic strategy is cell replacement therapy using cell differentiation/reprogramming to turn different cells sources into β-cells by mimicking embryonic development. Using the mouse as a model, we previously showed that embryonic pancreatic glucagon-producing cells can regenerate and convert into insulin-producing β-like cells through the constitutive/ectopic expression of a single gene, Pax4 (a gene involved in the embryonic specification toward the β-cell fate). More recently, we demonstrated that the misexpression of Pax4 in glucagon-expressing cells age-independently induces their conversion into β-like cells. The regenerative capacity of glucagon-producing cells and their potential for conversion into β-like cells by the simple ectopic expression of Pax4 are of interest in the context of type 1 diabetes research. However, this transgenic approach would be an impractical approach in humans. We therefore initiated a number of screens aiming to discover small molecules/chemical compounds mimicking the effects of the ectopic expression of Pax4. Methods: The compound X was found to induce the conversion of a majority of α-cells into β-like cells in vitro. In vivo tests were then initiated using Glu-Cre::Rosa26-lox-β-gal mice. These mice, where glucagon-expressing cells are irreversibly marked, were treated with a high dose of streptozotocin and then daily injected (or not) with the compound X once they were hyperglycemic. Results: In the animals treated with the compound X (isolated 40 days post-streptozotocin injection), islets appeared regenerated and further immunohistochemical analyses using antibodies raised against insulin and beta-galactosidase outlined a majority of cells positive for insulin and beta-galactosidase. Conclusion: Using lineage tracing experiments, we demonstrated that, upon compound X addition, β-like cells are regenerated following streptozotocin treatment, these deriving from cells that expressed the glucagon hormone.

47

CHASSOT Anne Amandine 2.2

Sex determination: genetic regulations of the gonadal plasticity CHASSOT Anne-Amandine (1,2), MAATOUK Danielle M. (3), GREGOIRE Elodie (1,2), CAPEL Blanche (3), CHABOISSIER Marie-Christine (1,2) (1) INSERM, U1091, CNRS UMR 7277, iBV, F-06108Nice, France (2) University of Nice-Sophia Antipolis, UFR Sciences, F-06108 Nice, France (3) Department of CellBiology, Duke University Medical Center, Durham, NC 27710, USA (corresponding author : chassot@unice.fr) Keywords : sex determination, plasticity, RSPO1, beta-catenin, mouse models Sex differentiation is a unique developmental process. Starting from a,bipotential gonad, it gives rise to the ovary and the testis, two very specialized organs that are morphologically and physiologically different despite sharing common reproductive and endocrine functions. This highlights the high plasticity of the gonadal precursors and the existence of complex and antagonistic genetic regulations. Mammalian sex determination is controlled by the paternal transmission of the Y-linked gene, SRY. Using mouse models, it has been shown that the main role of Sry is to activate the expression of the transcription factor Sox9, and these two genes are necessary and sufficient to allow testicular development through Sertoli cell differentiation. Thus, defects in SRY and/or SOX9 expression result in male-to-female sex reversal of XY individuals. In the XX individuals, the activation of the WNT4/beta-catenin signaling pathway by the secreted protein RSPO1 is required to allow ovarian development through granulosa cell differentiation. Thus, defects in RSPO1 and WNT4 expression result in female-to-male sex reversal of XX human patients. In Rspo1 and Wnt4 mutant mice, pregranulosa cells transit through a differentiated granulosa cell state prior to transdifferentiating towards a Sertoli cell fate. This transdifferentiation is closely associated with the regulation of the granulosa cell cycle that is under the influence of signals from neighbouring germ cells. So far, these signals remain to be identified. We will discuss here the respective roles of SRY/SOX9 and RSPO1/beta-catenin signalling pathways and present the current model of the genetics regulating mammalian sex determination.

48

LE THUC Ophélia 2.3

Role of the chemokine RANTES/CCL5 in the establishment of high-fat Diet-Induced Obesity in mice LE THUC Ophélia (1), BLONDEAU Nicolas (1), ROUAUD Florian (1), POITOU Christine (2), CLEMENT Karine (2), GUYON Alice (1), PITTALUGA Anna (3), HEURTEAUX Catherine (1), NAHON Jean-Louis (1), ROVERE Carole (1) (1) CNRS UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France. (2) INSERM, Nutriomique U872, Université Pierre et Marie Curie Paris 6, Paris, France. (3) Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, Genoa, Italy. (corresponding author : rovere@ipmc.cnrs.fr) Keywords : chemokine signaling, neuropeptides, obesity, neuroinflammation, feeding behavior Aims: Recent studies show, in a murine high-fat Diet-Induced Obesity (DIO) model, a hypothalamic inflammation apparently essential to develop leptin resistance which participates in the maintenance of overweight. Moreover, recent data suggest that pro-inflammatory cytokines and/or chemokines could alter the peptidergic neuronal systems that control food intake. We investigate here the inflammatory factors effects on the setting up and maintenance of DIO, and on variations of expression of neuropeptides involved in feeding behaviour. Methods: C57BL6/J mice were fed either a control or a high-fat diet (HFD) for 8, 12 or 16 weeks and we collected blood and hypothalami after sacrifice. Expression levels of pro-inflammatory cytokines/chemokines and peptides involved in food intake were measured by qPCR and FACS Array. Results: The HFD consumption induces obesity and an increase of circulating pro-inflammatory cytokines levels. The chemokine RANTES circulating level, and its cerebral expression, are significantly increased in HFD mice vs. control mice. Interestingly, circulating RANTES concentration was 8 times higher in obese patients vs. control patients. Moreover, an acute central injection of RANTES in mice induces an increase of orexigenic peptides expression and mRNA levels, and a significant weight gain. Furthermore, we have revealed, by patch-clamp, a RANTES depolarizing effect on MCH neurons activity, through glutamate release, from neurons and glial cells, onto MCH neurons. Conclusion: Our results suggest that RANTES could participate, maintaining overfeeding through indirect action on MCH neuronal systems, in the deregulated central food intake control. RANTES could represent a potential therapeutic target in the treatment of diet-induced obesity. This work is supported by the Fondation pour la Recherche Médicale (FRM) and the Centre National de la Recherche Scientifique (CNRS).

49

MAGRINELLI Elia 2.4

Post-mitotic control of sensory area specification during neocortical development MAGRINELLI Elia (1,2,3), ALFANO Christian (1,2,3), HARB Kawssar (1,2,3), HEVNER Robert (4), STUDER Michele (1,2,3) (1) Univ. Nice Sophia Antipolis, iBV, UMR 7277, 06108 Nice, France (2) Inserm, iBV, U1091, 06108 Nice, France (3) CNRS, iBV, UMR 7277, 06108 Nice, France (4) Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98101, USA (corresponding author : elia.magrinelli@gmail.com) Keywords : neocortex, development, neurobiology, arealization, differentiation The neocortex is the largest region of the mammalian cerebral cortex and is dedicated to the highest brain functions such as thought and voluntary movement. This structure is subdivided radially in six neuronal layers and tangentially in several domains deputed to the elaboration of sensory and motor inputs. The process subdividing the neocortex in these functional areas is called arealization and starts at early stages of corticogenesis. Previous studies identified a series of genes expressed in progenitors of the cortex which are important for the correct specification of functional areas. COUP-TF1fl/fl-Emx1-Cre (EmxCKO) brains lose COUP-TFI expression in cortical cells resulting in an ectopic formation of sensory caudally with an expansion of rostral motor domain. Other studies focused on genes expressed only in post-mitotic cells of the cortex showing that a final refinement of functional areas can still happen after cortical cells exited proliferation, nonetheless it was still not clear how much of the cortical organization can happen after proliferation. In this study we analyse by different genetic, biomolecular and axon-labeling techniques the COUP-TF1fl/fl-Nex-Cre (NexCKO) brains, where COUP-TFI is ablated only in differentiating neurons of the cortex, without affecting proliferating cells. We also analyse brains in which COUP-TFI is expressed ectopically on a COUP-TFI null background. Our aim is to show that functional areas of the cortex are specified sufficiently after the end of proliferation. This study will give new insights on corticogenesis allowing the discovery of new targets for therapies aimed to cure neurodevelopmental diseases.

50

MORATAL Claudine 2.5

Resident adipogenic progenitors in human skeletal muscle : interactions with myogenic progenitors and like-macrophages MORATAL Claudine (1), DANI Christian (1), DECHESNE A. Claude (1) (1) CNRS UMR 7277 - INSERM U 1091 Institut de Biologie Valrose, Campus Valrose, Université Nice Sophia Antipolis, Nice, France (corresponding author : cmoratal@unice.fr) Keywords : myogenic progenitors, adipogenic progenitors, macrophages, inflammatory factors, growth factors In recent years, new adipogenic progenitors (APs) have been identified in human skeletal muscle. Unlike myogenic progenitors (MPs), they exclusively differentiate into adipocytes. On the basis of different results, APs are considered as the main contributor to intramuscular adipocyte infiltrations observed in myopathies. Recent studies in mice have pointed out cross-talks between APs and MPs regulations. Inflammation mediators are also potential important actors since the inflammatory process has a crucial role in muscle reparation. This project focuses on APs/MPs interactions and APs regulation by MPs and/or inflammatory cells like macrophages. For investigations on interactions between APs and MPs, we developed a co-culture system wherein the differentiation medium allows both adipogenic and myogenic differentiations. In these conditions, and only for progenitor cells derived from young donor muscles, we showed a stimulation of MPs myogenesis and an inhibition of APs adipogenesis. The stimulation of MPs differentiation seems to be dependant to cell-to-cell contacts with APs whereas inhibition of APs adipogenesis is mainly mediated by soluble factors. In addition to the effects of APs/MPs interactions on differentiations, we observed an increase of APs proliferation in presence of MPs conditioned medium and a decrease of MPs proliferation with APs conditioned medium. Finally, we screened a panel of soluble factors and three factors, HGF, IGF-1 and TNFα, were found to be important candidates as cytokines to explain APs/MPs interactions. To study interactions between macrophages with MPs and APs, we used the THP-1 human monocytic cell line. We induced macrophagic differentiation of THP-1 cells with phorbol myristate acetate and collected conditioned medium of mature macrophages. In the presence of macrophage-conditioned medium, MPs proliferation and differentiation were not affected, whereas APs proliferation and differentiation were significantly decreased, suggesting an essential role of inflammatory factors secreted by macrophages on APs regulation. These new findings on the impact of APs on myogenic differentiation of MPs and the APs regulation by MPs and macrophages in healthy human muscle shed new lights on the role of the recently discovered APs as well as a deeper understanding of muscle homeostasis. This work is supported by the Association Française contre les Myopathies through the research grant #16063 and a PhD fellowship for MORATAL C.

51

REINGOLD Victoria 2.6

Adenine methylation may contribute to endosymbiont selection in a clonal aphid population REINGOLD Victoria (1), DOMBROVSKY Aviv (2), ROBICHON Alain (1) (1) INRA/ CNRS/ UNSA University Nice Sophia Antipolis, 400 routes de Chappes Sophia Antipolis 06903 BP 167, France. (2) ARO The Volcani Center, Department of Plant Pathology, Beit Dagan 50250, Israel. (corresponding author : alain.robichon@sophia.inra.fr) Keywords : Acyrthosiphon pisum, bacteriocytes, facultative/secondary bacteria, epigenetic, deoxyadenosine methylase (dam) The pea aphid Acyrthosiphon pisum has two modes of reproduction; it is parthenogenetic during the spring and summer and reproduces sexually in autumn. This ability to alternate between reproductive modes and the emergence of clonal populations under favorable conditions make this organism an interesting model for genetic and epigenetic studies. The pea aphid hosts different type of endosymbiotic bacteria helping the aphids to survive and adapt to new conditions. The obligate endosymbiont Buchnera aphidicola has a drastically reduced genome; whereas facultative endosymbionts such as Regiella insecticola retain phages and mobile elements and have high levels of genetic recombination (1). In previous work, selection toward cold adaptation of parthenogenetic A. pisum orange variants, resulted in the appearance of individuals characterized by green abdomen pigmentation (2). Results: adenine-methylated DNA fragments were isolated from genomic DNA extracted from the cold-induced green variant using specific restriction enzymes for deoxyadenosine methylase (dam) analysis in GATC sites. The A1 fragment that encodes a putative transposase was selected for further comparison of the two A. pisum variants (green and orange) based on dam analysis followed by PCR amplification. Conclusions: A strict correlation was found, as indicated by higher adenine methylation levels at the GATC sites within the transposase gene in the green variant as compared to the orange variant. This high degree of adenine methylation demonstrated at 8ºC is reversible and disappears at 22ºC. Temperature selection may affect the secondary endosymbiont and the sensitive dam, involved in the survival and adaptation of aphids to cold temperatures. We found that dormant symbiosis mechanisms can be selected to increase host fitness under unfavorable climate conditions and the phenotype of the newly adapted aphids could be inherited. References: (1) Anderson JO, Anderson SGE: Insights into the evolutionary process of genome degradation. Current Opinion in Genetics & Development 1999, 9:664-671. (2) Dombrovsky, A., Arthaud, L., Ledger, T.N., Tares, S., Robichon, A. (2009). Profiling the repertoire of phenotypes influenced by environmental cues that occur during asexual reproduction. GenomeResearch. 19(11):2052-2063.

52

VIEIRA Andhira 2.7

Inducible misexpression of Ngn3 in pancreatic duct-lining cells VIEIRA Andhira (1,2), BEN OTHMAN Nouha (1,2), COURTNEY Monica (1,2), DRUELLE Noémie (1,2), GJERNES Elisabet (1,2), FAURITE Biljana (1,2), AVOLIO Fabio (1,2), NAPOLITANO Tiziana (1,2), FERRER Jorge (3) and COLLOMBAT Patrick (1,2) (1) Université de Nice-Sophia Antipolis, FR-06108 Nice, France (2) Inserm U1091, IBV, Equipe génétique du diabète, FR-06108 Nice, France (3) Hospital Clinic, IDIBAPS, Barcelona, Spain (corresponding author : collombat@unice.fr) Keywords : diabetes, endocrine pancreas, neurogenin3, transdifferentiation, mouse Background and aims: In the search for improved therapies for type 1 diabetes, a large amount of research has involved replenishing the beta-cell mass from cells already present within the pancreas whether it be in the exocrine or endocrine compartment. We have previously shown that the misexpression of Pax4 in glucagon-expressing/alpha-cells leads to their conversion into functional insulin-expressing cells displaying most features of true beta-cells. This conversion was accompanied by increased proliferation in the ductal epithelium and lining and a reactivation of the proendocrine marker Ngn3. These results led to the hypothesis that cells within the ductal epithelium re-express Ngn3, differentiate into glucagon-expressing cells and are subsequently converted into beta-like cells. Thus, the objective of the current project is to investigate the potential of cells from the ductal epithelium/lining to differentiate into endocrine cells by the sole forced expression of Ngn3. Methods: In order to specifically target duct cells within the pancreas, Hnf1β -CreER animals were used as HNF1β is solely expressed in duct cells of the mouse pancreas. This line was then crossed with a mouse line allowing the Cre-mediated expression of Ngn3 in duct cells upon tamoxifen treatment. The resulting animals are healthy, show no developmental issues or gain of weight and display normal basal glycaemia. In order to optimize the induction of Ngn3 in this system, different methods of tamoxifen administration and different times of treatment have been tested. Results: After short time treatment by gavage in these animals, our preliminary results indicate modest islet hyperplasia. Monitoring endocrine cell contents in these islets and in those of animals treated for longer time, this hyperplasia seems to be the result of an increase in all endocrine cells type, consistent with the role of Ngn3 in pancreatic development. Further characterization of these animals is ongoing at the level of islet architecture as well as at the functional level. These ongoing experiments will be presented. Conclusion: This ongoing work will help us determine whether ductal cells within the pancreas have the ability to differentiate into endocrine cells upon the sole activation of Ngn3.

53

VIOLLET Sébastien 2.8

Purification and characterization of ribonucleoprotein particles associated with the L1 ORF1p protein. VIOLLET Sébastien (1,2,4), PISANO Sabrina (1,2), CRISTOFARI Gaël (1,2,3,4) (1) Institute for Research on Cancer and Aging (IRCAN), Nice, France (2) INSERM, U1081, Nice, France (3) CNRS, UMR 7284, Nice, France (4) University of Nice-Sophia-Antipolis, Faculty of Medicine, Nice, France. (corresponding author : sebastien.viollet@unice.fr) Keywords : Plasticity, Retrotransposons, ORF1p assembly, Atomic force microscopy, L1 RNP The Long Interspersed Nuclear Elements 1 (LINE-1 or L1) are abundant non-LTR retrotransposons in the human genome. Active L1 elements code for two proteins: a 40 kDa trimeric RNA binding protein named ORF1p, and a large protein, ORF2p, which exhibits endonuclease and reverse transcriptase activities. These proteins assemble in cis with their own encoding mRNA to form a stable ribonucleoprotein particle (L1 RNP), which is the core of the L1 retrotransposition machinery. After its assembly, it is imported into the nucleus, where new L1 copies will be synthesized and integrated at new genomic DNA loci, through a coordinated mechanism called target-primed reverse transcription (TPRT). To get further insights into the composition and biogenesis of L1 RNPs, we fused an epitope tag to the ORF1p protein in a plasmid-borne replication-competent L1 element. After expressing this tagged-L1 in human cells, we applied affinity chromatography to purify soluble native L1 complexes assembled in vivo. We confirmed that L1 RNA and ORF2p co-purify with ORF1p. Atomic force microscopy (AFM) revealed large structures, which might correspond to ORF1p-RNPs. In addition, we are exploring the ability of ORF1p proteins to bind in cis or in trans on L1 RNAs by cotransfecting tagged and untagged elements. Our work will bring a more detailed view of the biogenesis of the retrotransposon core machinery. Work in the laboratory of G.C. is supported by INSERM and INCa (Avenir program), by the European Research Council (ERC Starting Grant ‘Retrogenomics’), and by the French Government (National Research Agency, ANR) through the "Investments for the Future" (LABEX SIGNALIFE, # ANR-11-LABX-0028-01). We are grateful to the IRCAN imaging core facility for providing access to atomic force microscopy.

54

Poster Session III, Axis 3 Stress Signaling

55

DANI Vincent 3.1

NPC proteins are key players in molecular interactions between cnidarians and their dinoflagellate endosymbionts DANI Vincent (1), REVEL Johana (1), PRIOUZEAU Fabrice (1), PAGNOTTA Sophie (2), CARETTE Diane (2), MERTZ Marjolijn (3), SABOURAULT Cécile (1) (1) Université de Nice-Sophia-Antipolis, UMR7138 Evolution Paris-Seine, Valrose, BP71, 06108 Nice Cedex 02, France (2) Centre Commun de Microscopie Appliquée, Université de Nice-Sophia-Antipolis, Nice, France (3) Plateforme d’imagerie PRISM, Institut de Biologie Valrose, Université de Nice-Sophia-Antipolis, Nice, France (corresponding author : Cecile.Sabourault@unice.fr) Keywords : Cnidarian, endosymbiosis, Niemann-Pick, communication, signaling Trophic endosymbioses between cnidarians and photosynthetic dinoflagellates form the key foundation of reef ecosystems. Cnidarians host their photosynthetic dinoflagellate symbionts within cells in the gastrodermal tissue layer. The establishment and maintenance of the symbiotic interaction is dependent on intimate molecular communications, including recognition and tolerance of symbionts, as well as adaptations for mutual transport and exchange of nutritional resources. However, environmental perturbations, such as an increase in seawater temperature, may disrupt this partnership, leading to the severe worldwide decline of coral reefs. Here, we will especially focus on the cholesterol-binding Niemann-Pick C proteins, which have been identified by transcriptomic analyses in symbiotic sea anemones. Cnidarians have a single copy of NPC1 (2 copies in vertebrates), whereas there are four copies of NPC2 (only one in vertebrates). We demonstrated that these copies arose from ancestral cnidarian-specific duplications. Moreover, the expression of the duplicate AvNPC2-D is up-regulated in symbiotic specimens, enhanced in the symbiotic cells (gastroderm), and strongly down-regulated in response to stresses that further led to the symbiosis collapse. Recently, several studies demonstrated the involvement of NPC proteins i) in innate immune pathways, such as the filovirus entry in mammalian cells1 and the binding of bacterial cell wall molecules in drosophila2, and ii) in chemical communication in worker ants, by binding numerous potential semiochemicals3. In symbiotic cnidarians, the NPC proteins could be involved in the recognition of the cell-surface glycans4 of dinoflagellates to allow their persistence within the symbiosomes. This may explain why several NPC2 have been retained in cnidarian genomes. This work is supported by the project inSIDE (ANR-12-JSV7-0009-01) 1. Carette, J. E. et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature 477, 340–343 (2011). 2. Shi, X.-Z. et al. Drosophila melanogaster NPC2 proteins bind bacterial cell wall components and may function in immune signal pathways. Insect Biochem. Mol. Biol. 42, 545–556 (2012). 3. Ishida, Y. et al. Niemann-Pick type C2 protein mediating chemical communication in the worker ant. Proc. Natl. Acad. Sci. (2014). 4. Logan, D. D. K. et al. Flow-Cytometric Characterization of the Cell-Surface Glycans of Symbiotic Dinoflagellates (symbiodinium Spp.)1. J. Phycol. 46, 5

56

LOUBIERE Camille 3.2

Metformin-induced energy deficiency leads to the inhibition of lipogenesis in prostate cancer cells LOUBIERE Camille (1), GOIRAN Thomas (1), LAURENT Kathiane (1), DJABARI Zied (1), TANTI Jean François (1), BOST Frédéric (1) (1) C3M, Centre Méditerranéen de Médecine Moléculaire INSERM U1065, Université de Nice Sophia Antipolis, Nice, France (corresponding author : bost@unice.fr) Keywords : prostate cancer, metformin, lipogenesis, metabolism, ATP Deregulation of lipid metabolism is a well recognized hallmark of cancer cells and elevated levels of lipogenic enzymes as well as increased lipogenesis has been reported in a wide variety of cancers, including prostate cancer. De novo fatty acid synthesis is required for the formation of the phospho-lipids of the membrane, especially in rapid growing cells. Retrospective epidemiological studies and preclinical data show that metformin, a drug commonly used in type II diabetes, displays antitumor properties. In this report, we investigated the effect of metformin on lipogenesis in prostate cancer. Using different in vitro approaches, we found that metformin inhibits lipogenesis in several prostate cancer cells. Prostate cancer is an hormone-dependent cancer, we demonstrate that metformin inhibits the pro-lipogenic effects of androgens. This inhibition of lipogenesis is not related to the decrease of key lipogenic enzyme expression, ACC (acetyl-CoA carboxylase) and FASN (Fatty acid synthase) or the transcription factor SREBP1c. Importantly, we showed that overexpression of a constitutive active form of SREBP1c which controls lipogenesis, doesn’t reverse the inhibitory effects of metformin on lipogenesis. Moreover, we observe no change in the concentration of the precursor of fatty acids, malonyl-CoA, which is regulated by the enzyme ACC. In addition, the level of NADPH, a co-factor required for lipogenesis, is not altered by metformin. Finally, we showed that the inhibition of lipogenesis is due to a cellular energy deficit. Indeed, lipogenesis is an energy consuming process which requires ATP. We show that ATP is reduced in a dose dependent in prostate cancer cells treated with metformin and this decrease is significantly correlated with a decrease of lipogenesis. In conclusion, our results describe a new mechanism of action of metformin in prostate cancer which could be implicated in metformin anti-proliferative action.

57

PRATX Loris 3.3

Identification of epigenetic marks in the plant parasitic root-knot nematode Meloidogyne incognita. PRATX Loris (1,2,3), PERFUS-BARBEOCH Laetitia (1,2,3), CASTAGNONE-SERENO Philippe (1,2,3), COSSEAU Céline (4,5), GRUNAU Cristoph (4,5), ABAD Pierre (1,2,3) (1) INRA, UMR 1355 ISA, Institut Sophia Agrobiotech, Sophia-Antipolis, France. (2) CNRS, UMR 7254 ISA, Institut Sophia Agrobiotech, Sophia-Antipolis, France. (3) Université de Nice Sophia-Antipolis, UMR ISA, Institut Sophia Agrobiotech, Sophia-Antipolis, France. (4) Université de Perpignan Via Domitia, Ecologie et Evolution des Interactions (2EI), Perpignan, France. (5) CNRS, UMR5244, Ecologie et Evolution des Interactions (2EI), Perpignan, France. (corresponding author : lpratx@gmail.com) Keywords : Meloidogyne incognita, Apomixis, Transgenerational epigenetic inheritance, Post-transcriptional histone modifications, ChIP-seq Root-knot nematodes, such as Meloidogyne incognita, are obligatory plant parasites that constitute major agricultural pests worldwide. Our knowledge about M. incognita’s genetics regulation has significantly increased since genome sequencing, transcriptomic analyses and genes annotation are available (1). However, despite this knowledge, the “classical” genetics fails to understand some phenomena occurring in our model. M. incognita reproduces in an asexual way by parthenogenesis without meiosis. Genetically identical individuals develop from females and form clonal populations. Although these clones share the same genetic heritage, modifications of their phenotype can be observed when they are exposed to unfavorable environments. For instance, the virulence (i.e. capacity to parasite a resistant crop) is heritable but transmitted in a non-Mendelian way (not acquired by 100% of the “clonal daughters”) and could not be associated to a modification in DNA sequence (2). Epigenetic modifications can drive phenotypes by other mechanisms than genetics. These modifications are heritable, but metastable, which could change phenotypes by modifying genomic expression. We propose to test the role of the epigenome in the generation of phenotypic variability and consequently for microevolution towards infection success. We detailed DNA methylation and nucleosome structure, carrier of epigenetic information. We also developed a ChIP-seq assay protocol to compare post-transcriptional histone modifications between virulent and avirulent parasites; and between different developmental stages. Our preliminary data indicated that the genome of M. incognita is not methylated and confirmed the existence of histone modifications which represents important markers involved in gene activation or repression by modifying chromatin state. This study opens the way for analyzing the role of epigenetic mechanisms at a whole-genome scale and identifying new biological processes involved in the generation of phenotypic variation in asexual organisms. 1 - Abad, P. et al. (2008) Genome sequence of the metazoan plant-parasitic nematode Meloidogyne incognita. Nature Biotechnology 26: 909-915 2 - Semblat, J. et al. (2000) Virulence and molecular diversity of parthenogenetic root-knot nematodes, Meloidogyne spp. Heredity 84: 81-89

58

ZUNINO Barbara 3.4

Role of antitumoral immunity in the treatment of peritoneal carcinomatosis ZUNINO Barbara (1,2,3), MEYNET Ophelie (1,3), VILLA Elodie (1,3), POMMIER Sebastien (1,2,3), RUBIO PATINO Camila (1,3), MONDRAGON Laura (1,3), VERHOYEN Els (1,3), CORNILLE Aurore (1,3), CHICHE Johanna (1,3), BEREDER Jean-Marc (2), BENCHIMOL Daniel (2), RICCI JE (1,2,3) (1) INSERM U1065, Team ”contrôle métabolique des morts cellulaires”, Nice, France (2) CHU de Nice, France. (3) Université de Nice Sophia-Antipolis, Nice, France (corresponding author : ricci@unice.fr) Keywords : colon cancer, HIPEC, Hsp, cytokine, vaccination Peritoneal carcinomatosis is a disease of digestive–tract cancer with a median survival of about 2 years. A new and very interesting therapeutic approach is to combine cytoreductive surgery with Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) leading to a median survival of 5 years. The aim of our work is to uncover how HIPEC could enhance the patient’s survival? We speculated that the immune system could participate in the protective effect brought by HIPEC in patients. Using murine colon carcinoma cell line (CT26), we generated an in vitro model of HIPEC allowing us to investigate the role played by the chemotherapy alone or in combination with hyperthermia. We established ex vivo that HIPEC and chemotherapy alone-treated cells could activate T cells. In addition when mice were immunized with HIPEC or chemotherapy alone-treated tumor cells, they could be protected from a subsequent challenge using the same tumor in viable form (anti-tumor vaccination assay). Surprisingly it seems that HIPEC is less efficient than chemotherapy alone in the vaccination of mice. Using in vitro, ex vivo and clinical samples, we could exclude the involvement of heat shock proteins (HSPs) in the observed effect. However we identified that key cytokines are differentially modulated upon treatment. We are currently investigating their contribution to the observed vaccination. Taken together, our results demonstrate that 1/ HIPEC and chemotherapy alone could vaccinate mice against tumor development 2/ that HIPEC-treated cells seems to be less efficient in the vaccination of mice compared to chemotherapy alone-treated cells. 3/ Cytokines but not Hsps seem to be implicated in the anti tumoral response.

59

Poster Session IV, Axis 4 Signaling in aging and disease Progression

60

ALBRENGUES Jean 4.1

Production of LIF cytokine by cancer cells and fibroblasts contributes to the establishment of a pro-invasive tumor microenvironment. ALBRENGUES Jean (1), BOURGET Isabelle (1), PONS Catherine (1), BUTET Vincent (2), TARTARE-DECKERT Sophie (3), FERAL Chloe (1), MENEGUZZI Guerrino (1) and GAGGIOLI Cedric (1). (1) INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging in Nice (IRCAN), University of Nice Sophia Antipolis, Medical School, 28 Avenue de Valombrose, F-06107, Nice, France. (2) Pathological anatomy and cytology laboratory, 270 Avenue Sainte-Marguerite, F-06200, Nice, France. (3) INSERM, U1065, Mediterranean Centre for Molecular Medicine (C3M), University of Nice Sophia Antipolis, Nice, France. (corresponding author : albrengues@unice.fr) Keywords : tumor microenvironment, carcinoma associated fibroblasts, cancer cell invasion, LIF cytokine Tumor-stroma signaling crosstalk contributes to tumor microenvironment modifications and cancer cell spreading. Carcinoma associated fibroblasts (CAF) display enhanced extracellular matrix remodeling capacities and formation of a pro-invasive tumor microenvironment, which enables carcinoma cell collective invasion. The TGFβ cytokine-dependent signaling pathway was considered the major CAF activator. Using three-dimensional organotypic invasion assays, we investigated the molecular mechanisms of the TGFβ1-dependent signaling that mediates the pro-invasive fibroblast activation. We demonstrate that TGFβ−induced LIF production by both cancer cells and fibroblasts is responsible for the pro-invasive tumor microenvironment modifications. LIF cytokine stimulation of human dermal fibroblasts activates pro-invasive track formation in a GP130/JAK1/STAT3 specific dependent signaling pathway. We show that LIF mediates TGFβ-dependent acto-myosin contractility leading to collagen fiber assembly. In subsequent screenings, 11 out of 12 human carcinoma cell lines from different organs (skin, head and neck, breast and colon) and 2 out of 3 human melanoma cell lines induce pro-invasive fibroblast activation in vitro through direct secretion of LIF. Moreover, detection of LIF cytokine in human carcinoma specimens indicated that LIF is significantly up-regulated in tumor tissues and correlated with poor clinical outcome. Finally, an orthotopic mice model of breast carcinoma demonstrates that LIF production correlates with tumor microenvironment collagen fiber organization and cancer cell invasion in vivo. These results disclose the molecular mechanisms underlying the pro-invasive activation of stromal fibroblasts in tumor contexts and identify LIF cytokine as a key player in the process. They also suggest that blocking JAK1 kinase expression in CAF may present potential therapeutic benefits for patients with aggressive carcinoma.

61

DUBOIS Nicolas 4.2

The deubiquitinating enzyme USP14 controls MCL-1 expression and leukemic cell survival DUBOIS Nicholas (1,2), MALLAVIALLE Aude (1,2), DELMONT Emilien (1,3), GAREL Maxence (1), JEANDEL Pierre-Yves (3), TICCHIONI Michel (1,3), TARTARE-DECKERT Sophie (1,2), and DECKERT Marcel (1,2) (1) INSERM, U1065, C3M, Équipe Microenvironnement, Signalisation et Cancer, Alpes-Maritimes, Nice, France (2) Université de Nice-Sophia Antipolis, Faculté de Médecine, Alpes-Maritimes, Nice, France (3) CHU Nice, Hôpital Archet, Alpes-Maritimes, Nice, France (corresponding author : Nicholas.DUBOIS@unice.fr) Keywords : Chronic Lymphocytic Leukemia, SYK, MCL-1, Deubiquitinating enzyme, USP14 Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western countries. CLL is characterized by the accumulation of neoplastic B cells in the blood, secondary lymphoid tissue and bone marrow. CLL cells show a reduced capacity to be eliminated by apoptosis. This phenomenon is supported by the genetic and epigenetic alterations inherent to the tumor cell , but also by the signals of the antigen receptor of B cells (BCR) and cell interactions with their microenvironment. At the molecular level , these processes are associated with a high expression of anti-apoptotic proteins of the BCL-2 family , and in particular of MCL- 1. In CLL, MCL-1 expression is associated with high resistance to chemotherapeutic agents and tumor progression. We and others have shown that spleen tyrosine kinase (SYK) and leukemic microenvironment provide survival signals preventing the degradation of MCL-1 by the ubiquitin-proteasome system (UPS). In order to identify deubiquitinating enzymes (DUBs), involved in MCL-1 degradation in leukemic cells, we have used a HA-tagged biochemical probe that covalently reacts with active DUBs from protein cell extracts. Consistent with increased MCL-1 levels, we found that BCR activation stimulates a pattern of active DUBs in B cell neoplasms. Short-term treatment of leukemic cells with cytotoxic agents, including the SYK and Burton's tyrosine kinase (BTK) inhibitors, decreased the DUB activity and MCL-1 levels, whereas the genotoxic compound doxorubicin had no gross effect neither on DUB activity nor MCL-1 expression. The enzymatic activation of DUBs in viable leukemic cells was confirmed using ubiquitin-AMC, a fluorogenic substrat of active DUBs and WP1130, a recently described DUB pharmacological inhibitor. Using biochemical approaches, we then identified ubiquitin specific protease (USP) 14 (USP14) as one of major active DUBs in leukemic cells. Inhibition of USP14 by WP1130 and IU1, a new specific USP14 inhibitor, reduce! d MCL-1 expression and cell survival measured by flow cytometry. In addition, depletion of USP14 by siRNA effectively reduced MCL-1, but not Bcl-2 or XIAP expression and increased leukemic cell death. Moreover, USP14 overexpression increased MCL-1 level. Together, our study indicates that the proteasome-associated USP14 deubiquitinating enzyme represents a novel key regulator of the antiapoptotic protein MCL-1 and underlines the interest of certain DUBs as potential therapeutic targets in CLL treatment.

62

EL MAI Mounir 4.3

The Telomeric Protein TRF2 is an Angiogenic Target of WT1 by Binding and Activating the PDFGRβ Promoter EL MAI Mounir (1), WAGNER Kay-Dietrich (1), MICHIELS Jean-François (1)(2), AMBROSETTI Damien (1)(2), BORDERIE Arnaud (2), DESTREE Sandrine (2), RENAULT Valerie (1), DJERBI Nadir (1), GIRAUD-PANIS Marie-Josèphe (1), GILSON Eric (1)(3), WAGNER Nicole (1) Institut for Research on Cancer and Aging, Nice (IRCAN), University of Nice Sophia-Antipolis, CNRS UMR7284/INSERM U1081, Faculty of Medicine, Nice, France (2) Department of Pathology, CHU Nice, Nice, France (3) Department of Medical Genetics, CHU Nice, France (corresponding author : elmai@unice.fr) Keywords : TRF2, WT1, Angiogenesis, PDGFRβ, cancer Telomeric repeat-binding factor 2 (TRF2), which plays a central role in telomere capping, is also frequently increased in human tumors. We reveal here that TRF2 is expressed in the vasculature of most human cancer types but could not be detected in the vessels of healthy adjacent tissues. In vitro TRF2 over-expression in Human umbilical vein endothelial cells (HUVEC) resulted in an increased proliferation and migration, while silencing of TRF2 led to the opposite results. No changes in apoptosis could be observed. It is worth noting that modulation of TRF2 does not change the level of DNA damage response and that the stimulation of endothelial cells is ATM –independent. The angiogenic effects of TRF2 are then uncoupled from its function in telomere capping. Since the transcription factor WT1 (Wilms’ tumour suppressor 1) is highly expressed in human tumour vessels in vivo and mediates angiogenic properties of endothelial cells, we investigated whether TRF2 expression could be regulated by WT1. Indeed, WT1 binds the TRF2 promoter and activates TRF2 transcription. Finally, we found that TRF2 binds and transactivates the promoter of the angiogenic tyrosine kinase PDGFRβ. These findings reveal an unexpected role of TRF2 in neoangiogenesis and delineate a distinct function of TRF2 as a transcriptional regulator.

63

ESTRACH Soline 4.4

CD98hc (SLC3A2) Loss Protects Against Ras-Driven Tumorigenesis Through Modulation of Integrin-Mediated Mechanotransduction ESTRACH Soline (1a), LEE Sin Ae (2), BOULTER Etienne (1a), PISANO Sabrina (1b), ERRANTE Aurelia (1a), TISSOT Floriane (1a), PONS Catherine (1a), GINSBERG Mark (2), FERAL Chloe (1a). (1) INSERM, U1081, CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), Avenir Team(a), AFM Core facility(b), University of Nice Sophia Antipolis, Medical School, 28 Avenue de Valombrose, F-06107, Nice, France. (2) Department of Medicine, University of California San Diego, La Jolla, CA 92093. (corresponding author : soline.estrach@inserm.fr) Keywords : CD98hc/SLC3A2, Ras-driven cancer, gain amplifier, Stiffness, YAP/TAZ The transmembrane glycoprotein CD98hc (SLC3A2), is highly expressed in many cancers and is associated with poor prognosis; however, knowledge on how CD98hc contributes to tumorigenesis remains incomplete. Here, we show, in a chemically-induced skin carcinogenesis, that CD98hc-deficient epidermis was protected against tumor formation. We demonstrate that CD98hc deletion led to regression of existing tumors. Furthermore, our studies reveal that two new functions of CD98hc contribute to epithelial cancer, beyond CD98 intrinsic effect on tumor cell proliferation. First, CD98hc increased the stiffness of the tumor microenvironment. Secondly, we report that CD98hc amplifies the capacity of cells to respond to matrix rigidity, an essential factor of tumor development. We show that CD98hc mediates this stiffness sensing by increasing Rho kinase (ROCK) activity in vivo resulting in increased transcription dependent on YAP/TAZ, the nuclear relays of mechanical signals. Therefore, CD98hc contributes to epidermal carcinogenesis by acting as a gain-amplifier of a positive feedback loop that increases both extracellular matrix stiffness and resulting cellular responses.

64

GACHE Yannick 4.5

Analysis of skin cancer development with the xeroderma pigmentosum model GACHE Yannick (1), AL-QARAGHULI Sahar (1), ROUANET Sophie (1), SCARZELLO Sabine (1), OHANNA Mickael (2), BERTOLOTTO Corinne (2), BALLOTTI Robert (2), MAGNALDO Thierry (1) (1) INSERM U1081 - CNRS UMR 7284 - IRCAN, Nice, France (2) INSERM U1065, C3M, Nice, France (corresponding author : gache@unice.fr) Keywords : Skin cancers, Ultraviolets, Microenvironment, XPC Our objectives are to study the mechanisms implicated in the development of human epithelial cancers among which skin cancers (squamous cell carcinoma, SCC, and malignant melanoma, MM) account for the most aggressive neoplasms. The ethiology of those cancers is clearly linked to exposure to genotoxic stesses, notably ultraviolet radiations (UVR). In addition, increasing evidence supports the idea that activation of stromal cells, notably dermal fibroblasts, in turn, promotes tumor cells agressiveness and invasive capacities. Xeroderma pigmentosum (XP-C) is a rare genetic disorder characterized by a severe predisposition to aggressive skin cancers following minimal exposure to UVR. XP-C cells are deficient in the nucleotide excision repair (NER) of DNA lesions introduced at bipyrimidine sequences following UVR. Beside a tremendous quantitative increase in skin cancer development, cancers in XP patients are particularly aggressive leading to compromised life expectency. On these clinical bases, we hypothetized that XP-C fibrobroblasts could further promote the agressiveness of patients cancers. We have analyzed the capacity of XP-C fibroblasts to promote migration and invasion of melanoma and carcinoma cells. Our results show that the secretome of XP-C fibroblasts elicited migration and invasion of SCC12/SCC13 cells, and of the non tumorigenic Mel501 melanoma cells in vitro. Treatment of Mel501 cells in culture supernatant of XP-C fibroblasts provoked tumorigenesis in mice. Invasion and tumor formation were abolished in genetically corrected XP-C fibroblasts. Screening of molecules secreted by XP-C fibroblasts identified Hepatocyte Growth Factor/Scatter Factor as a potential pro-invasive/tumorigenic factor. Culture supernatants from XP-C fibroblasts activated the c-Met signaling pathways in SCC and Mel501 cells. Our studies demonstrate an important role for XP-C fibroblasts in tumor progression and identify factors responsible for the formation of a permissi! ve micro environment.

65

GILLERON Jérôme 4.6

The small GTPase Rab4b in lymphocytes controls glucose metabolism in mice GILLERON Jérôme (1), DJEDAINI Mansour (1), CORNEJO Pierre-Jean (1), CEPPE Franck (1), JACQUEL Arnaud (2), NEBOUT Marielle (3), IMBERT Véronique (3), DUMAS Karine (1), TANTI Jean-François (1), CORMONT Mireille (1) (1) C3M U1065, Team 7, Nice, France (2) C3M U1065, Team 2, Nice, France (3) C3M U1065, Team 4, Nice, France (corresponding author : cormont@unice.fr) Keywords : Rab4b, obesity, insulin resistance, immuno-métabolism, type 2 diabetes A low grade inflammatory state in obese adipose tissue (AT) is involved in insulin resistance development. T lymphocytes are key players in connecting AT inflammation to insulin resistance. Governing intracellular trafficking, small GTPase Rab proteins play a pivotal role in the regulation of cellular functions in all cells, including T lymphocytes. We found a reduction of Rab4b expression in obese mice and humans AT as well as in T lymphocytes from blood and AT of obese mice. Thus, we aimed at determining whether a decreased expression of Rab4b in T lymphocytes plays a role in insulin resistance by impacting on lymphocyte functions. For that, we generated Rab4blymphoT-/- mice invalidated for Rab4b in T lymphocytes by crossing Rab4bflox/flox mice with Lck-Cre mice (specific promoter for T lymphocyte). We determined their metabolic phenotype and characterized the T lymphocyte sub-populations in the thymus, spleen, blood and AT, as well as their endocytic functions. Under a high fat died, 25-week old control and Rab4blymphoT-/- mice get similar weight but Rab4blymphoT-/- mice are more insulin resistant and liver steatosis is increased. Under a normal diet, 25-week-old Rab4blymphoT-/- mice evince slight modifications of glucose and lipid homeostasis. Compared to control mice, AT weights are similar but adipocytes are hypertrophied. ATs are infiltrated by pro-inflammatory macrophages and the expression of proteins involved in insulin action in adipocytes is decreased, indicating that adipocytes are insulin resistant. However, the mice are glucose tolerant and are not insulin resistant. Strikingly, older mice (35-week-old) become glucose intolerant and insulin resistant. How a depletion of Rab4b in lymphocyte could impact on AT metabolism? We found that the number of CD4+Foxp3+ Treg lymphocytes was decreased in AT. This lymphopenia was systemic (blood, spleen, thymus) and possibly due to an increased apoptosis that occurred more likely during T lymphocyte positive selection. Mechanistically, this defect could be caused by alterations of endosome morphology and function that leads to a decrease of TCR at the T-cell plasma membrane. The loss of Rab4b in T lymphocytes impacts on their biogenesis and induces a remodeling of AT that could participate during aging in the development of insulin resistance. Also, the perturbed functions of AT aggravate the gluco-lipidic parameters when mice are challenged with a high fat diet.

66

GUAL Phillipe 4.7

OSTEOPONTIN DEFICIENCY AGGRAVATES HEPATIC INJURY INDUCED BY ISCHEMIA-REPERFUSION IN MICE PATOURAUX S (1,2,3)*, ROUSSEAU D (1,2)*, RUBIO A (1,2)*, BONNAFOUS (1,2,4), LAVALLARD VJ (1,2), LAURON J (1,2), SAINT-PAUL MC (1,2,3), BAILLY-MAITRE B (1,2), TRAN A (1,2,4), CRENESSE D (1,2,5), GUAL P (1,2) §. (1) INSERM, U1065, Centre Méditerranéen de médecine Moléculaire (C3M), Équipe 8 « Complications hépatiques de l’obésité», Nice, France (2) Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France (3) Centre Hospitalier Universitaire de Nice, Pôle Biologique, Hôpital Pasteur, Nice, France (4) Centre Hospitalier Universitaire de Nice, Pôle Digestif, Hôpital L'Archet, Nice, France (5) Centre Hospitalier Universitaire de Nice, Hôpitaux Pédiatriques CHU Lenval, Nice, France (corresponding author : gual@unice.fr) Keywords : osteopontin, ischemia-reperfusion, hepatic injury, hepatocyte, macrophage Osteopontin (OPN) is a multifunctional protein involved in hepatic steatosis, inflammation, fibrosis and cancer progression. However, its role in hepatic injury induced by ischemia-reperfusion (I-R) has not yet been investigated. We show here that hepatic warm ischemia for 45 min followed by reperfusion for 4 h induced the up-regulation of the hepatic and systemic level of OPN in mice. Plasma AST and ALT levels were strongly increased in Opn-/- mice compared with wild-type mice after I-R and histological analysis of the liver revealed a significantly higher incidence of necrosis of hepatocytes. In addition, the expression level of iNOS, TNFα, IL6 and IFNγ was strongly up-regulated in Opn-/- mice versus wild-type mice after I-R. One explanation for these responses could be the vulnerability of the OPN deficient hepatocyte. Indeed, the down-regulation of OPN in primary and AML12 hepatocytes decreased cell viability in the basal state and sensitized AML12 hepatocytes to cell death induced by oxygen-glucose deprivation and TNFα. Further, the down-regulation of OPN in AML12 hepatocytes caused a strong decrease in the expression of anti-apoptotic Bcl2 and in the ATP level. The hepatic expression of Bcl2 also decreased in Opn-/- mice versus wild-type mice livers after I-R. Another explanation could be the regulation of the macrophage activity by OPN. In RAW macrophages, the down-regulation of OPN enhanced iNOS expression in the basal state and sensitized macrophages to inflammatory signals, as evaluated by the up-regulation of iNOS, TNFα and IL6 in response to lipopolysaccharide. In conclusion, OPN partially protects from hepatic injury and inflammation induced in this experimental model of liver I-R. This could be due to its ability to partially prevent death of hepatocytes and to limit the production of toxic iNOS-derived NO by macrophages.

67

HINAULT Charlotte 4.8

Activated brown adipose tissue in young progeny of protein restricted rat dams permits the maintenance of glucose homeostasis HINAULT Charlotte (1,2)*, DUMORTIER Olivier (1)*, CASAMENTO Virginie (1), GAUTIER Nadine (1), JOHNSTON Hereroa (1), PISANI Didier (3), VAN OBBERGHEN Emmanuel (1,2) * These authors contributed equally to this work (1) IRCAN, INSERM U1081, CNRS UMR 7284, UNS, 06107 Nice, France. (2) Research and develpment, Biochemistry Laboratory, University Hospital, Nice, France (3) IBV, UMR 7277, UNS, 06100 Nice, France. (corresponding author : vanobbeg@unice.fr) Keywords : Fetal Programming, Type 2 Diabetes, Obesity, Insulin Resistance, Brown Adipose Tissue Both epidemiological studies in humans and animal models reveal that the intrauterine environment of the fetus is a preeminent actor in long-term health. Indeed, mounting evidence shows that maternal malnutrition increases the risk of type 2 diabetes (T2D) in progeny. In rat dams, protein restriction alters in the progeny the development of the endocrine pancreas and favors the appearance of insulin resistance with age leading to T2D later in life. At 3 months of age progeny of pregnant rats fed a low protein (LP) diet are glucose intolerant due to insufficient insulin secretion. However, they become hyperglycemic and insulin resistant at a later age. As brown adipose tissue (BAT) is known to clear excess fuel energy, we evaluate here its potential role in the preservation of normoglycemia in young LP progeny. To do so we challenged starting from weaning 3 month-old control and LP progeny with a high fat diet (HFD). Compared to control progeny exposed to HFD, LP progeny gain less weight and do not develop liver steatosis. Remarkably, under HFD LP progeny have an increase in BAT mass, which is hyperactive and presents augmented levels of the uncoupling protein UCP1 allowing energy dissipation as heat. In fact, even on standard diet LP progeny have hyperactive BAT with increased UCP1 expression. Therefore, in preliminary experiments, we evaluated the BAT status in cells differentiated from progenitors. Compared to control cells, the LP differentiated BAT cells seem to have increased activity pointing to its programming by the maternal environment. This amplified BAT activation in LP progeny plays an important role in organismal homeostasis as its waning coincides with the appearance of insulin resistance. Further, we reveal the misexpression of a series of microRNAs in the BAT of 3 month-old LP progeny, which could explain the adaptive changes in BAT. To summarize, we suggest that in young LP progeny suffering from decreased insulin secretion the augmented B! AT activ ity dissipates the excessive fuels allowing energy homeostasis, and hence provides a mechanism to protect against obesity and its associated insulin resistance.

68

LOUET Jean-François 4.9

Hepatic SRC-1 Activity Orchestrates Transcriptional Circuitries of Amino Acid Pathways with Potential Relevance for Human Metabolic Pathogenesis TANNOUR-LOUET Mounia (1,2), *, YORK Brian (1) *, TANG Ke (1), XU Jianming (1), NEWGARD Christopher B. (4), O’MALLEY Bert W. (1), #, $ and LOUET Jean-Francois (1,5) (1) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030 (2) Department of Urology, Baylor College of Medicine, Houston, TX 77030 (3) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030 (4) Sarah W. Stedman Nutrition and Metabolism Center and Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27704 (5) Centre Méditerranéen de Médecine Moléculaire, INSERM U1065, Nice, France (corresponding author : jflouet@unice.fr) Keywords : Transcriptional Coactivators, Amino Acids Homeostasis, Nuclear Receptors, Human Metabolic Diseases Disturbances in amino acid metabolism are increasingly recognized as being associated with, and serving as prognostic markers for chronic human diseases such as cancer or type 2 diabetes. In the current study, a quantitative metabolomics profiling strategy revealed global impairment in amino acid metabolism in mice deleted for the transcriptional coactivator SRC-1. Aberrations were hepatic in origin, since selective re-expression of SRC-1 in the liver of SRC-1 null mice largely restored amino acids concentrations to normal levels. Cistromic analysis of SRC-1 binding sites in hepatic tissues confirmed a prominent influence of this coregulator on transcriptional programs regulating amino acid metabolism. More specifically, SRC-1 markedly impacted tyrosine levels and was found to regulate the transcriptional activity of the tyrosine aminotransferase (TAT) gene, which encodes the rate-limiting enzyme of tyrosine catabolism. Consequently, SRC-1 null mice had low TAT expression and presented with hypertyrosinemia and corneal alterations, two clinical features observed in the human syndrome of TAT deficiency. A heterozygous missense variant of SRC-1 (p.P1272S) that is known to alter its coactivation potential, was found in patients harboring idiopathic tyrosinemia-like disorders and may therefore represent one risk factor for their clinical symptoms. Hence, we reinforce the concept that SRC-1 is a central factor in the fine orchestration of multiple pathways of intermediary metabolism, suggesting it as a potential therapeutic target that may be exploitable in human metabolic diseases and cancer.

69

MARTIN Pauline 4.10

Anti-proteases target cancer stem cells expressing an embryonic signature and decrease their tumour potential MARTIN Pauline (1), DARINI Cédric (1), AZOULAY Stéphane (2), DRICI Milou-Daniel (3), HOFMAN Paul (4), DANI Christian (1), LADOUX Annie (1) (1) CNRS Université de Nice Sophia-Antipolis, Institut de Biologie Valrose, Nice, France (2) CNRS Université de Nice Sophia-Antipolis, Institut de Chimie, Nice, France (3) CHU Université de Nice Sophia-Antipolis, Département de Pharmacologie, Nice, France (4) INSERM Université de Nice Sophia-Antipolis, IRCAN, Nice, France (corresponding author : pauline.martin@unice.fr) Keywords : Cancer Stem Cells, HIV-protease inhibitors, Stemness signature, Apoptosis, Oct-4 Objectives Cancer stem cells (CSCs) constitute a specific subset of the cancer cell population in the majority of solid tumours. They play a key role in self-renewal sustaining tumour growth and metastasis. Among them, CSCs displaying an embryonic stem cell “stemness” signature based on the expression of Oct-4, Nanog and Sox2, are present in distinct high grade tumour types associated with poor prognosis. In this study, molecules targeting CSCs specifically were identified as potential therapeutic agents to reduce malignant progression, then preventing tumour recurrence. Material We set up a model to isolate pure populations of CSCs expressing an embryonic signature from distinct solid tumours 1. They were isolated from spontaneously developing solid tumours obtained from p53-/- mice expressing GFP and the puromycin resistance gene under the control of the Oct-4 promoter. Molecules were screened to specifically reduce their proliferation as compared to the total population of cancer cells isolated from the same tumour and to induce cell death. The efficiency to impair CSCs tumour potential was evaluated by allograft formation assays in immune-deficient mice. Results We show that HIV-protease inhibitors (HIV-PIs) specifically target CSCs expressing an embryonic signature. They reduced proliferation in a dose-dependent manner with higher specificity and efficiency as compared to the total population of cancer cells and they were efficient to induce cell death. Lopinavir (LPV) was the most effective HIV-PIs among those tested. Structure-activity relationship experiments allowed the identification of essential pharmacophores for LPV-antitumour specificity and activity. LPV-induced CSCs death was accompanied by the expression of activated-caspase 3 and cleavage of the DNA repair enzyme PARP-1, which represents a hallmark of apoptosis. In addition, in vivo treatment of mice with a fixed association of lopinavir and ritonavir resulted in a reduction of allografts formation, indicating a beneficial effect on tumour regression. Conclusions These results contribute to the identification of molecules presenting selective toxicity for CSCs expressing an embryonic stemness signature 2. This offers promising therapeutic opportunities for patients suffering from solid cancer tumours of poor prognosis. References 1 Darini C, Dani C, Ladoux A, (2012) Oncogene 31: 2438-49. 2 Darini C, Martin P, Dani C, Ladoux A (2013) Cell Death Dis. doi10.1038/cddis.2013.206

70

MOURGUES Lucas 4.11

Bmi1 represses a tumour suppressive autophagic response mediated by a cyclin G2-PP2A-PKCζ signalling module. MOURGUES Lucas (1,2,5), MARY Didier (1,2,5), IMBERT Véronique (1,2), NEBOUT Marielle (1,2), COLOSETTI Pascal (1,2), NEFFATI Zouhour (1,2), LAGADEC Patricia (1,2), PENG Chun (3), DUPREZ Estelle (4), PEYRON Jean-François (1, 2). (1) INSERM, UMR1065, Centre Méditerranéen de Médecine Moléculaire C3M, Nice 06204, France (2) Université de Nice-Sophia Antipolis, UFR Médecine, Nice, France (3) Department of Biology, York University, Toronto, Ontario, Canada (4) INSERM, U1068, Centre de Recherche en Cancérologie de Marseille CRCM, Marseille 13273, France (5) These authors contributed equally to this work (corresponding author : mary@unice.fr) Keywords : Epigenetic repression, Bmi1 polycomb protein, cyclin G2, Tumour suppressive autophagy, Protein phosphatase 2A-PKCζ complex Bmi1 is a polycomb protein involved in the epigenetic repressive control of essential cellular functions such as proliferation, senescence, metabolism and self-renewal in both hematopoietic and cancer stem cell. Overexpression of Bmi1 prevents senescence and apoptosis of transformed cells and is associated with an unfavourable prognosis in numerous cancers. This pro-tumoural effect is usually mediated by the repression of Bmi1 main target, the locus Ink4a. Also there are situations for which an increase in Bmi1 during cancer progression towards more aggressive states (Cao et al., 2011) is concomitant with a loss of Ink4a, one of the most frequently lost gene in human cancer (30% of cases) (Kim and Sharpless, 2006). As such, the chronic myeloid leukaemia (CML) blast crisis is associated with the acquisition of additional genetic defects, such as the loss of Ink4a/ARF function after the methylation-dependent silencing of p16ink4a and p14Arf gene promoters, while at the same time, expression levels of Bmi1 in CML primitive cells increased gradually (Bhattacharyya et al., 2009). Altogether, these observations strongly suggest that Bmi1 could control other important loci, in particular tumour suppressor ones. We used the K562 CML cellular model that harbours a deletion of Ink4a to search for new modes of action for Bmi1. Here we demonstrate that Bmi1 supports proliferation and clonogenicity by repressing an autophagic response that depends on expression of CycG2. Indeed, our work shows that when Cyclin G2 is derepressed it is able to compete with protein phosphatase 2A subunit to release an active form of PKCζ which then activates several autophagic pathways such as AMPK, JNK and ERK. Our results highlight a new function for Bmi1 that could be relevant to the physiopathology of hematopoietic stem cells and leukemic stem cells. This work is supported by the Société Française d’Hématologie (SFH). Cao, L., Bombard, J., Cintron, K., Sheedy, J., Weetall, M.L., and Davis, T.W. (2011). BMI1 as a novel target for drug discovery in cancer. Journal of cellular biochemistry 112, 2729-2741. Kim, W., and Sharpless, N. (2006). The regulation of INK4/ARF in cancer and aging. Cell 127, 265-275. Bhattacharyya, J., Mihara, K., Yasunaga, S., Tanaka, H., Hoschi, M., and Kimura, A. (2009). Bmi-1 expresion is enhanced through transcriptional and posttranscriptional regulation during the progression of chronic myeloid leukemia. Ann Hematol 88, 333-340.

71

POTTIER Anaïs 4.12

The role of tumor cell-derived SPARC in mTORC2/AKT-mediated p53 regulation and resistance of melanoma cells to V600EBRAF inhibition POTTIER Anaïs (1,2), FENOUILLE Nina (4), DECKERT Marcel (1,2), TARTARE-DECKERT Sophie (1,2). (1) Inserm, U1065, Centre Méditerranéen de Médecine Moléculaire, Nice, France. (2) Université de Nice – Sophia Antipolis, Faculté de Médecine, Nice, France. (3) Koch Institute for Cancer Research-MIT, Cambridge,USA (corresponding author : sophie.Tartare-Deckert@unice.fr) Keywords : Melanoma, V600EBRAF mutation, resistance, SPARC, AKT Oncogenic mutations in BRAF are the most represented in human melanoma. To date specific V600EBRAF inhibitors (Vemurafenib or Dabrafenib) fail to cure the metastatic disease due to development of mechanisms of acquired resistance. Tumor microenvironment is often implicated in drug resistance, and contributes to AKT pathway activation in melanoma. We prevently showed in our laboratory that a matricellular protein secreted by melanoma cells, SPARC, is responsible for elevated of AKT signaling and promotes an autocrine loop that confers survival advantage through suppression of p53-dependent apoptosis. In this study we have investigated the interplay between SPARC, AKT signaling and p53 in primary and acquired resistance to BRAF inhibitors. We found that overexpression of SPARC in V600EBRAF-mutated melanoma cells attenuates sensitivity to Vemurafenib and Dabrafenib and to chemotherapy-induced cytotoxicity. Conversely, knockdown of SPARC by siRNA cooperates with BRAF inhibitors to promote clonogenic cell death. Mechanistically, SPARC knockdown was found to decrease phosphorylation of Rictor/mTORC2 a key upstream component of AKT, which is associated with decreased phosphorylated MDM2 and activation of p53. To better understand the role of SPARC in resistance to BRAF inhibitors, we analyzed its levels in V600EBRAF melanoma sublines with acquired resistance to Dabrafenib. We found that development of resistance is associated with increased SPARC and phosphorylated AKT, and a decrease in p53 protein level, which are reversed upon SPARC depletion by siRNA. Importantly, we found that extinction of SPARC expression resensibilises Vemurafenib resistant cells to a sub-lethal dose of Vemurafenib. Furthurmore, inhibition of the B-RAF target MEK with a sub-lethal dose of U0126 induces apoptotic and clonogenic death of SPARC-depleted Dabrafenib resistant cells. Our findings indicate that the level of SPARC is a determinant of therapeutic sensitivity of melanomas. Furthermore this study emphasizes the interest of targeted inhibition of SPARC in combinatory strategies to overcome BRAF inhibitor resistance.

72

PROD'HOMME Virginie 4.13

3bp2 cherubism mutation amplifies TLR signaling in mouse macrophage PROD'HOMME Virginie (1,3), BOYER Laurent (2,3), DUBOIS Nicholas (1,3), MALLAVIALLE Aude (1,3), MOUSKA Xavier (3),ROTTAPEL Robert (4), TARTARE-DECKERT Sophie (1,3) and DECKERT Marcel (1,3). (1) INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Team "Microenvironment, Signaling and Cancer", Nice, France (2) INSERM, U1065, C3M, Team "Microbial toxins in host pathogen interactions", Nice, France (3) Université de Nice Sophia-Antipolis, Faculté de Médecine, Nice, France (4) Ontario Cancer Institute, Toronto Medical Discovery Tower, Toronto, Canada (corresponding author : prodhomme@unice.fr) Keywords : 3BP2, Cherubism, Macrophages, Inflammation Cherubism is a rare autoinflammatory bone disorder associated with point mutations in the SH3BP2 gene coding for the adapter protein 3BP2. The disease is characterized by symmetrical fibro-osseous lesions of the jaw, attributed to exacerbated osteoclast activation and defective osteoblast differentiation. Although a dominant trait in human, cherubism appears to be recessively transmitted in mice, suggesting the existence of additional factors in the pathogenesis of cherubism. Here, we report that 3bp2 deficient mouse macrophages exhibited dramatically reduced inflammatory responses to bacterial challenge and reduced phagocytosis, both in vivo and in vitro. 3bp2 was necessary to LPS-induced activation of crucial signaling components of macrophage function, including Src, Vav1, p38, Ikkα/β, Rac and actin polymerization. Conversely, we show that TLR4 stimulation and one sh3bp2 cherubic allele have a dramatic cooperative effect on macrophage activation and inflammatory responses in mouse. Our study in mouse genetic models supports the notion that bacterial infection may represent a driver event in the etiology of cherubism in human, thereby suggesting new potential therapeutic options.

73

REPETTO Emanuela 4.14

RNY-derived small RNAs are novel biomarkers for Coronary Artery Disease REPETTO Emanuela (1), HIZIR Zoheir(1), TRABUCCHI Michele(1) (1) INSERM, U 1065, Centre Méditerrannéen de Médecine Moléculaire, Nice, France (corresponding author : erepetto@unice.fr) Keywords : small RNAs, macrophage, atherosclerosis, coronary artery disease, biomarker

Significant amounts of small RNAs, including microRNAs, have been recently found in extracellular body fluids, including blood, urine, saliva, and semen. Some circulating miRNAs in the blood have been successfully revealed as biomarkers for several human disorders, such as many cancers, cardiovascular diseases, and brain and liver injuries. During the past 2 years my team demonstrated that the ~110 nt long cytoplasmic Ro-associated non-coding RNAs, called RNYs, are processed to small 24-34 nt sequences in macrophages upon pro-atherogenic or pro-apoptotic treatments. The expression of s-RNYs were measured in a subsample of 45 male patients with stable Coronary Artery Disease (CAD) and 45 age-matched healthy male subjects, in the context of a case-control study (Bouisset et al. 2012, The American journal of cardiology 110: 197). Metabolic and clinical variables of the cohort were previously checked. We found a significant upregulation of at least 2 s-RNYs in CAD patients (p<0.001). Correlation between s-RNY levels and individual metabolic parameters and cardiovascular risk markers were investigated. s-RNYs were positively correlated with pro-atherogenic lipids (triglycerides and LpB:E) and negatively with HDL markers. Environmental factors, such as physical activity and inflammation, documented by CRP level, displayed positive correlation. Overall, these data indicate a strong correlation between 2 s-RNYs and CAD risk (94% and 88% of ROC curves, respectively), supporting the hypothesis that s-RNYs measurement might improve CAD risk prediction. This work has been supported by ANR through the “Investments for the Future” # ANR-11-LABX-0028-01 (LABEX SIGNALIFE) to M.T. and P.B, by ANR Emergence and GENO #102 01 to L.O.M., and by ANR-10-INBS-09-03 (France-Génomique) to P.B. L.L. is supported by Marie Curie IEF program.

74

ROUANET Sophie 4.15

Role of the XPC protein in the development of cutaneous cancers ROUANET Sophie (1), GONCALVES Maria (1), GACHE Yannick (1), WARRICK Emilie (2), LARCHER Fernando (3), Del RIO Marcela (3), MAGNALDO Thierry (1) (1) INSERM U1081 - CNRS UMR 7284- UNS, IRCAN, Nice, France (2) L'Oreal Research and Innovation, Clichy, France (3) CIEMAT, Madrid, Spain (corresponding author : srouanet@unice.fr) Keywords : Skin cancers, UV, NER, XPC

Somatic stem cells are the origin of tissue renewal, healing in case of injury, and probably cancer development following exposure to genotoxic agents. Ultraviolet radiations (UVs) from sunlight are the major etiological factor of skin cancers. Exposure to UVs, notably UVB, generate mutagenic DNA lesions at bipyrimidine sequences; these lesions are repaired by the nucleotide excision repair (NER) mechanism. Xeroderma pigmentosum (XP-C) is a rare genetic disorder due to a defect in NER. XP patients are highly photosensitive and prone to cutaneous cancers in photo-exposed skin. XP skin cells constitute a highly sensitive model to analyze the mechanisms involved in cancer development. We have regenerated XP-C skin onto SCID mice and first studied the effects of acute UVB irradiation. Under these circumstances, invasive epidermal structures developed after 3 months and exhibited substantial alterations of differentiation as observed in human carcinomas. Conversely, skin regenerated from genetically corrected XP-C keratinocytes presented a normal histology and proper features of differentiation and stratification. To study the effects of chronic UVB, XP-C keratinocytes were submitted to low doses irradiations. The clonogenic potential of chronically irradiated keratinocytes was dramatically increased compared to irradiated controls. Sequential irradiations also allowed us to isolate atypical keratinocytes clones that genome stucture and expression is under study. Skin regeneration from these “UV-primed” cells will reveal their neoplastic potential. For the first time, these studies will allow us to decipher the sequence of genetic alterations and their consequences upon acute and UV carcinogenesis in the human.

75

TICHET Mélanie 4.16

Tumor-derived SPARC activates endothelial VCAM1 signaling to induce vascular permeability and drive cancer cell extravasation and distant metastasis TICHET Mélanie (1,2), FENOUILLE Nina (1,2), PROD’HOMME Virginie (1,2), CEREZO Michaël (2,3), OHANNA Mickaël (2,3), MALLAVIALLE Aude (1,2), ROCCHI Stéphane (2,3), ALLEGRA Maryline (2,3), DECKERT Marcel (1,2), and TARTARE-DECKERT Sophie (1,2,§) (1) INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Microenvironnement, Signalisation et Cancer, Nice, France. (2) Université de Nice - Sophia Antipolis, Faculté de Médecine, Nice, France. (3) INSERM, U1065, C3M, Biologie et Pathologies des Mélanocytes, Nice, France. (corresponding author : tartare@unice.fr) Keywords : melanoma, metastasis, SPARC, extravasation, vascular permeability Cutaneous melanoma is one of the most aggressive cancers capable of distant and lethal metastatic spread. Tumor cell intravasation into blood vessel at primary tumor sites and subsequent extravasation are critical steps in the formation of metastases. These steps entail disruption of the endothelial barrier by tumor cells to facilitate their transendothelial passage and metastatic seeding. However, the way by which tumor cells modulate vascular junction integrity is still poorly understood. In an attempt to determine permeability factors secreted by metastatic cells, we identified the matricellular protein SPARC as a critical signaling factor that contributes to elevated vascular permeability and tumor cell extravasation. SPARC is highly produced by invasive melanoma and cell-autonomous SPARC signaling promotes invasion by inducing tumoral EMT and favors melanoma survival by inhibiting p53 tumor suppression function but its contribution to later stages of the metastatic cascade such as tumor-endothelial cell interactions and extravasation remained unexplored. By modeling in vitro the transmigration process between metastatic melanoma from short-term cultures or cell lines and primary vascular endothelial cells, we show SPARC released by melanoma cells enhances vascular leakiness by inducing opening of intercellular junctions of endothelial monolayers and drives melanoma cell transendothelial migration. In vivo vascular permeability and metastatic assays using fluorescence and biomuminescence imaging demonstrate that SPARC deficiency abrogates tumor-induced permeability of lung capillaries and prevents extravasation from blood vessels and metastasis, whereas overexpression of SPARC increases the lung metastatic potential of melanoma cells. Mechanistically, SPARC-induced endothelial gap formation and transmigration is dependent on vascular cell adhesion molecule (VCAM1) and p38 MAPK signaling pathway in endothelial cells. Importantly, blocking VCAM1 impedes ! melanoma cell extravasation. The clinical relevance of our findings is highlighted by the high levels of SPARC detected in tumor cells from human pulmonary melanoma lesions. Together, our results implicate tumor cell SPARC and its counter receptor VCAM1 in regulation of lung extravasation and shed light on novel mechanisms underlying transendothelial migration of melanoma cells. This work provide a rationale and mechanistic basis for targeting SPARC to inhibit melanoma metastases.

76

Poster Session V, Axis 5 New principles in signaling and applications

77

CATOZZI Simona 5.1

Downstream versus upstream stimulus-responses in biochemical signaling cascades CATOZZI Simona (1), SEPULCHRE Jacques-Alexandre (1) (1) Institut Non Linéaire de Nice, Valbonne, France (corresponding author : simona.catozzi@inln.cnrs.fr) Keywords : Cascades, Retroactivity, Modeling, Upstream Signaling, Target-off effects We present a perspective of new principle of intracellular signaling. Our work is under early development, and our goal is to prompt possible experimental works to associate to our theoretical development, with possible applications in the field of drug design. The representation of signaling cascades implicitly conveys the idea of unidirectionality of signal propagation. However, [1] shows that an intrinsic feedback (retroactivity) emerges naturally, so that a cascade can actually exhibit bidirectional propagation. Moreover, recent experiments [2] confirm some of our theoretical predictions [3] and show that the retroactive effects may not be negligible. Notably, some off-target effects can arise when kinase inhibitors are used in anti-cancer therapies [4]. Therefore we propose to study a new type of signaling, that we call upstream signaling in contrast with the usual downstream signaling that is naturally considered in a cascade. The “signal” of the upstream signaling would be a kinase inhibitor acting at the bottom of the cascade and the “response” would be the phosphorylated protein fraction at the top of the cascade. In the simplest case of a 2-stage signaling cascade, we show that by changing the concentration of the phosphatase acting on the second stage, one can switch between the two forms of signaling, downstream to upstream, and vice-versa. Then, in an arbitrary long signaling cascade, we propose a theoretical approach to compare the two forms of signaling. One can show that the dose-response curve (downstream signaling) and drug-response curve (upstream signaling) can be computed by means of two iterative maps that are roughly inverse from each other. In the current literature, there is no study about the parameter conditions of a signaling pathway, that would compare downstream versus upstream signaling. Would such parameter conditions be mutually exclusive? That would partly explain why the idea of upstream signaling has so far been overlooked compared with downstream signaling. [1] A. C. Ventura, J. A. Sepulchre, and S. D. Merajver. PLoS Comput Biol, 4(3):e1000041, 2008. [2] T. Jesan, U. Sarma, S. Halder, B. Saha, and S. Sinha. PloS one, 8(5):1–12, 2013. [3] J.-A. Sepulchre, S. D. Merajver, and A. C. Ventura. PloS one, 7(7):e40806, 2012. [4] M. L. Wynn, A. C. Ventura, J. A. Sepulchre, H. J. Garcia, and S. D. Merajver. BMC Syst Biol, 5:156, 2011.

78

ZUBIOLO Alexis 5.2

Neuron classification from 3-D confocal microscopic images ZUBIOLO Alexis (1*), HARB Kawssar (2), LUKIANETS Nikita (2,3), GRAMMONT Franck (3), STUDER Michèle (2), DEBREUVE Eric (1*), DESCOMBES Xavier (4*) (1) Univ. Nice Sophia Antipolis, CNRS, I3S, UMR 7271, 06900 Sophia Antipolis, France (2) Univ. Nice Sophia Antipolis, iBV, UMR Inserm U1091, CNRS 7277 06108 Nice, France (3) Univ. Nice Sophia Antipolis, Laboratoire J.A. Dieudonné, UMR CNRS 7351, 06108 Nice, France (4) INRIA, Sophia Antipolis (*) Team Morpheme, INRIA CRI-SAM / I3S / iBV (corresponding author : alexis.zubiolo@i3s.unice.fr) Keywords : cortical projection neurons, layer V, mathematical morphology, segmentation, classification The mammalian neocortex is organized into six neuronal layers distinguished by their connectivity, morphology, molecular code and cytoarchitecture. Each layer is constituted by different neuronal populations; for example, layer V neurons consist of two major types of projection neurons (PNs): corticofugal (subcerebral and corticostriatal) and corticocortical (callosal) PNs. We are interested in characterizing a distinct subpopulation of layer V PNs using molecular and morphometric parameters. To this end, we use the well-characterized Thy1-eYFP-H transgenic line that labels layer V subcerebral PNs from P14 onwards. The purpose of this work is to develop an image processing workflow to automatically characterize the size, shape and soma-dendritic morphology of layer V YFP+ neurons, and categorize them according to their morphological and molecular profiles. For each sample, the imaging protocol produces a low-resolution image (used to extract the apical dendrites of the neurons) and several high-resolution images providing close ups of the somas. Information from these two image sets must be combined to solve the classification problem. The proposed methodology is composed of the following steps. 1. High resolution images are registered onto the low-resolution image so that identical neurons match each other. This consists in matching a subset of points given by the location of somas in the high-resolution image in the whole set of points given by the location of somas in the low-resolution image. 2. On high-resolution images, the somas and the bases of their dendrites are segmented using some tools from the mathematical morphology approach. 3. From this segmentation, some morphological features of the neurons are computed. 4. Based on these features, the neurons are classified into categories in an unsupervised fashion using a k-means algorithm. 5. The apical dendrite of each neuron will be detected on the low-resolution image using a combination of a marked point process detection model in 2D slice and a graph-based tracking algorithm to reconstruct the 3D geometry. Geometrical features such as branching point will be computed. This framework will provide a classification of the neurons individually. Finally, the different samples will be analyzed and characterized in terms of the proportion of neurons in the different obtained classes.

79

LIST OF PARTICIPANTS

No. Last Name First Name Research institute or laboratory Function Email Phone SIGNALIFE member special participant Presentation Axis

1 ABAD Pierre ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

abad@sophia.inra.fr 04 92 38 66 02 Yes

2 ACOSTA LOPEZ Maria Isabel C3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

miacosta@unice.fr 06 27 10 82 13 Yes

3 AGRAWAL Neha iBV - Institut de Biologie Valrose Post-doc agrawal@unice.fr 04 92 07 64 43 Yes

4 AILHAUD Gérard iBV - Institut de Biologie Valrose Researcher / Lecturer

ailhaud@unice.fr 07 59 13 05 30 Yes

5 ALBRENGUES Jean IRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

albrengues@unice.fr 06 98 22 46 19 Yes talk 4

6 ALQARAGHULI SaharIRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

alqaraghuli@unice.fr 04 93 37 76 27 Yes

7 ANDRIO Emilie C3M - Centre Méditerranéen de Médecine Moléculaire

Post-doc andrio@unice.fr 04 89 06 42 62 Yes talk 1

8 ANTONNY BrunoIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

antonny@ipmc.cnrs.fr 04 93 95 77 75 Yes SIGNALIFE Keynote

Lecture talk 1

9 ARNAUD JacquelC3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

jacquel@unice.fr 04 89 06 43 06 Yes

10 ARRIGHI Nicole iBV - Institut de Biologie Valrose Researcher / Lecturer

nicole.arrighi@unice.fr 04 93 37 70 38 Yes

11 AUBERGER Patrick C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

auberger@unice.fr 04 89 06 43 11 Yes

12 AVELLA Martine iBV - Institut de Biologie Valrose Researcher / Lecturer

avella@unice.fr 04 92 07 68 57 Yes Organizer

13 BALLOTTI Robert C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

ballotti@unice.fr 04 89 06 43 32 Yes Organizer

14 BARBRY PascalIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

barbry@ipmc.cnrs.fr 04 93 95 77 93 Yes

15 BARNAY-VERDIER Stéphanie SYMAR - Symbiose MarineResearcher / Lecturer

stephanie.barnay-verdier@upmc.fr

04 92 07 68 43 No

16 BARRAL Yves ETH Zurich Researcher / Lecturer

yves.barral@bc.biol.ethz.ch + 41 44 632 0678 NoInvited Keynote

Lecture talk 1

17 BARRE BenjaminIRCAN - Institute for Research on Cancer and Aging, Nice

Master student

byngeamain@gmail.com 06 46 86 02 59 Yes

18 BECK Konstanze UNS - Université Nice Sophia Antipolis Engineer kbeck@unice.fr 04 92 07 69 98 Yes Organizer

19 BEN JOUIRA RaniaC3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

rania.benjouira@gmail.com 07 60 75 03 09 Yes

20 BEN OTHMAN Nouha iBV - Institut de Biologie Valrose PhD student

benothman@unice.fr 06 79 05 39 43 Yes talk 2

21 BERTACCHI Michele iBV - Institut de Biologie Valrose Post-doc michelebertacchi@hotmail.com 06 01 67 40 82 Yes

22 BESSE Florence iBV - Institut de Biologie Valrose Researcher / Lecturer

besse@unice.fr 04 92 07 64 34 Yes Organizer

23 BIGAY Joëlle IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

bigay@ipmc.cnrs.fr 04 93 95 77 72 Yes

24 BONAN Stéphanie IRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

bonan.stephanie@gmail.com 06 46 38 08 01 Yes

25 BOSSELUT-BENOIT Nathalie ISA - Institut Sophia Agrobiotech, INRA Engineer Nathalie.Bosselut@sophia.inra.fr 04 92 38 64 58 Yes

26 BOULAKIRBA SoniaIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

PhD student

boulakirba@ipmc.cnrs.fr 04 93 95 77 73 Yes poster 1

27 BOULTER Etienne IRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

boulter@unice.fr 06 07 18 81 35 Yes poster 1

28 BOURDELY PierreIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

PhD student

pierre.bourdely@gmail.com 06 50 82 83 43 Yes

29 BOYER LaurentC3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

boyerl@unice.fr 04 89 06 42 44 Yes

30 BREST PatrickIRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

brest@unice.fr 04 92 03 12 45 Yes Organizer

31 CAILLETEAU LaurenceIRCAN - Institute for Research on Cancer and Aging, Nice

Engineer caillete@unice.fr 06 70 29 62 74 Yes

32 CAPOVILLA Maria ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

Maria.Capovilla@sophia.inra.fr 06 33 93 29 54 Yes

33 CASSE Frédéric IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Post-doc casse@ipmc.cnrs.fr 04 93 95 34 62 Yes

34 CATOZZI Simona Institut Non Linéaire de Nice PhD student

simona.catozzi@inln.cnrs.fr 06 98 22 90 95 No poster 5

35 CEPPO FranckC3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

Franck.Ceppo@unice.fr 04 89 06 42 37 Yes talk 4

36 CHASSOT Anne Amandine iBV - Institut de Biologie Valrose Researcher / Lecturer

chassot@unice.fr 04 92 07 64 18 Yes talk 2

37 CHEREL Pierre iBV - Institut de Biologie Valrose Engineer cherel@unice.fr 04 92 07 64 68 Yes

38 CHERFILS-VICINI JulienIRCAN - Institute for Research on Cancer and Aging, Nice

Post-doc julien.cherfils@unice.fr 04 93 37 70 19 Yes talk 4

39 CHEVALIER Marlène LSBV-CHU-UNS -Laboratoire Santé Buccale et Vieillissement

PhD student

marlene.chevalier@unice.fr 04 92 00 13 64 No

40 CHICHE JohannaC3M - Centre Méditerranéen de Médecine Moléculaire

Post-doc chiche@unice.fr 04 89 06 43 01 Yes talk 3

41 CHINH NGHIA Nguyen ISA - Institut Sophia Agrobiotech, INRAPhD student

chinh-nghia.nguyen@sophia.inra.fr

06 40 20 57 12 Yes

42 CLEMENT Karine INSERM, ParisResearcher / Lecturer

karine.clement@psi.aphp.fr 01 42 17 79 28 NoInvited Keynote

Lecture talk 2

43 CLEMENT Mathilde ISA - Institut Sophia Agrobiotech, INRA Post-doc mathilde.clement@sophia.inra.fr 04 92 38 64 19 Yes talk 2

44 COLLOMBAT Patrick iBV - Institut de Biologie Valrose Researcher / Lecturer

collombat@unice.fr 04 92 07 64 16 Yes

45 COLOMBANI Julien iBV - Institut de Biologie Valrose Researcher / Lecturer

colomban@unice.fr 04 92 07 64 43 Yes

46 CORMONT Mireille C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

cormont@unice.fr 04 89 06 32 34 Yes

47 COURTNEY Monica iBV - Institut de Biologie Valrose Post-doc monica.courtney@unice.fr 04 92 07 64 56 Yes

48 CRISTOFARI GaelIRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

gael.cristofari@unice.fr 04 93 37 70 87 Yes

No. Last Name First Name Research institute or laboratory Function Email Phone SIGNALIFE member special participant Presentation Axis

49 DA SILVA Fabio iBV - Institut de Biologie Valrose PhD student

fdasilva@unice.fr 04 92 07 64 73 Yes

50 D'ANGELO Gisela iBV - Institut de Biologie Valrose Researcher / Lecturer

dangelo@unice.fr 04 92 07 64 58 Yes

51 DANI Vincent Institut de Biologie Paris-Seine UMR 7138 Evolution Paris Seine

PhD student

vincent.dani@unice.fr 06 09 40 07 71 No talk 3

52 DANI Christian iBV - Institut de Biologie Valrose Researcher / Lecturer

dani@unice.fr 04 93 37 76 47 Yes Organizer

53 DECHESNE Claude iBV - Institut de Biologie Valrose Researcher / Lecturer

dechesne@unice.fr 06 13 78 39 67 Yes

54 DECKERT MarcelC3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

deckert@unice.fr 04 89 06 43 10 Yes

55 DELANOUE Rénald iBV - Institut de Biologie Valrose Researcher / Lecturer

delanoue@unice.fr 04 92 07 64 43 Yes

56 DELAUNAY Franck iBV - Institut de Biologie Valrose Researcher / Lecturer

delaunay@unice.fr 04 92 07 68 38 YesSIGNALIFE Keynote

Lecture talk 5

57 DELGADILLO Roberto IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Post-doc delgadillo@ipmc.cnrs.fr 07 81 21 37 44 Yes

58 DINIZ Giovanne University of São Paulo Master Student

giovanne.diniz@usp.br +5511963687129 No

59 DJABARI ZiedC3M - Centre Méditerranéen de Médecine Moléculaire

Engineer djabari@unice.fr 04 89 06 42 29 Yes

60 DOYE AnneC3M - Centre Méditerranéen de Médecine Moléculaire

Engineer doye@unice.fr 04 89 06 42 63 Yes

61 DRUELLE Noémie iBV - Institut de Biologie Valrose PhD student

ndruelle@unice.fr 04 92 07 64 56 Yes

62 DUBOIS NicolasC3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

Nicholas.DUBOIS@unice.fr 04 89 06 43 13 Yes poster 4

63 EL HACHEM Najla C3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

Najla.EL-HACHEM@unice.fr 06 83 97 97 00 Yes

64 EL MAI Mounir IRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

elmai@unice.fr 06 27 43 94 53 No poster 4

65 ESTRACH SolineIRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

soline.estrach@inserm.fr 04 93 37 70 32 Yes poster 4

66 FAVERY Bruno ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

bruno.favery@sophia.inra.fr 04 92 38 64 64 Yes Organizer

67 FAVRE GuillaumeIRCAN - Institute for Research on Cancer and Aging, Nice

Clinician favre@unice.fr 06 83 10 26 93 Yes

68 FERAL ChloéIRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

chloe.feral@inserm.fr 04 93 37 76 18 Yes

69 FOUCHER KevinIRCAN - Institute for Research on Cancer and Aging, Nice

Master student

kfoucher83@gmail.com 06 88 01 86 47 No poster 1

70 FRANCO Michel IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

franco@ipmc.cnrs.fr 04 93 95 77 77 Yes

71 FRENDO Pierre ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

frendo@unice.fr 04 92 38 66 38 Yes Organizer

72 FÜRTHAUER Maximilian iBV - Institut de Biologie Valrose Researcher / Lecturer

furthauer@unice.fr 04 92 07 64 39 Yes Organizer

73 GACHE Yannick IRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

gache@unice.fr 06 69 11 49 37 Yes poster 4

74 GAGGIOLI Cedric IRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

gaggioli@unice.fr 04 93 37 77 53 Yes

75 GALANTONU RamonaIRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

Ramona.GALANTONU@unice.fr 06 34 48 69 82 Yes

76 GARCIA RODAS Rocio iBV - Institut de Biologie Valrose Post-doc rocio.garcia-rodas@unice.fr 07 82 29 45 17 Yes

77 GILLERON Jérôme C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

jerome.gilleron@unice.fr 04 89 06 42 34 Yes talk 4

78 GILLOT Isabelle iBV - Institut de Biologie Valrose Researcher / Lecturer

gillot@unice.fr 04 92 07 64 22 Yes

79 GIORDANO Cécile iBV - Institut de Biologie Valrose PhD student

cegiordano@unice.fr 06 22 58 12 27 Yes poster 1

80 GIRARD Christophe C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

chgirard@unice.fr 04 89 01 43 13 Yes

81 GIROUD Maude iBV - Institut de Biologie Valrose PhD student

mgiroud@unice.fr 06 88 47 81 52 No poster 1

82 GONCALVES-MAIA MariaIRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

maria.goncalves-maia@unice.fr 06 48 62 52 50 Yes

83 GORE Thanvi iBV - Institut de Biologie Valrose Post-doc Tanvi.Gore@unice.fr 04 92 07 64 43 Yes poster 1

84 GOUZE Jean-LucInria - Centre de Recherche Inria Sophia Antipolis - Méditerranée

Researcher / Lecturer

jean-luc.gouze@inria.fr 04 92 38 78 75 Yes

85 GRASSET Eloïse IRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

eloise.grasset@unice.fr 06 87 33 14 27 Yes

86 GUAL PhillipeC3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

gual@unice.fr 04 89 06 42 23 Yes poster 4

87 GWIZDEK CaroleIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

gwizdek@ipmc.cnrs.fr 04 93 95 34 62 Yes

88 HAFNER Anne-Laure iBV - Institut de Biologie Valrose PhD student

alhafner@unice.fr 04 93 37 76 65 Yes poster 2

89 HAHN Klaus University of North CarolinaResearcher / Lecturer

khahn@med.unc.edu+ 1 919-843-2775

NoInvited Keynote

Lecture talk 5

90 HALLIN Johan IRCAN/ University of Gothenburg Master Student

johan.h.hallin@gmail.com 07 05 24 01 56 Yes

91 HAMAOUI Daniel C3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

dhamaoui@unice.fr 06 23 78 02 39 Yes

92 HARB Kawssar iBV - Institut de Biologie Valrose PhD student

kawssar.harb@unice.fr 06 80 02 79 52 Yes poster 1

93 HAUPAIX NicolasLBDV - Laboratoire de Biologie du développement de Villefranche

PhD student

haupaix.nicolas@gmail.com 06 61 12 43 32 No

94 HINAULT Charlotte IRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

hinault@unice.fr 04 93 37 77 33 Yes poster 4

95 HOFMAN PaulIRCAN - Institute for Research on Cancer and Aging, Nice

Clinician hofman.p@chu-nice.fr 04 92 03 88 55 Yes

96 HOK Sophie ISA - Institut Sophia Agrobiotech, INRA Post-doc sophie.hok@sophia.inra.fr 04 92 38 64 64 Yes

No. Last Name First Name Research institute or laboratory Function Email Phone SIGNALIFE member special participant Presentation Axis

97 HUEBER Anne-Odile iBV - Institut de Biologie Valrose Researcher / Lecturer

hueber@unice.fr 06 12 04 21 2 Yes

98 JAUBERT-POSSAMAI Stephanie ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

stephanie.jaubert@sophia.inra.fr

06 62 21 45 49 Yes

99 KELLER Harald ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

keller@sophia.inra.fr 04 92 38 65 94 Yes Organizer

100 KHAYACHI Anouar IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

PhD student

khayachi@ipmc.cnrs.fr 04 93 95 34 62 Yes

101 KOOTAR ScherazadIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

PhD student

kootar@ipmc.cnrs.fr 06 08 05 61 31 Yes

102 KOUIDHI Magali iBV - Institut de Biologie Valrose Engineer magali.kouidhi@unice.fr 06 71 94 80 95 Yes

103 LABBAOUI Hayet iBV - Institut de Biologie Valrose PhD student

hlabbaoui@unice.fr 06 17 91 30 79 Yes

104 LAHAYE Thomas Universität Tübingen, GermanyResearcher / Lecturer

Thomas.lahaye@zmbp.uni-tuebingen.de

+49 (0)7071 29 78745

NoInvited Keynote

Lecture talk 3

105 LAMBEAU Gerard IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

lambeau@ipmc.cnrs.fr 04 93 95 77 33 Yes

106 LAPEBIE Pascal LBDV - Laboratoire de Biologie du développement de Villefranche

Post-doc lapebie@obs-vlfr.fr 06 74 23 49 47 No

107 LE THUC Ophélia IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

PhD student

lethuc@ipmc.cnrs.fr 04 93 95 77 41 Yes poster 2

108 LEBEAUPIN CynthiaInstitut des Maladies Neurodégénératives de Bordeaux

Master Student

clebeaupin@mac.com 06 42 02 08 93 No

109 LEBOUCHER Antoine IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Post-doc leboucher@ipmc.cnrs.fr 06 85 87 42 16 Yes

110 LECLERC Justine iBV - Institut de Biologie Valrose Master student

justine160608@hotmail.fr 06 51 28 13 85 Yes

111 LEMICHEZ Emmanuel C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

lemichez@unice.fr 04 89 06 42 61 Yes Organizer

112 LEOPOLD Pierre iBV - Institut de Biologie Valrose iBV leopold@unice.fr 06 37 61 20 82 YesSIGNALIFE Keynote

Lecture talk 1

113 LITI GianniIRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

gianni.liti@unice.fr 04 93 37 76 72 Yes

114 LLORED AgnèsIRCAN - Institute for Research on Cancer and Aging, Nice

Engineer Agnes.LLORED@unice.fr 04 93 37 77 28 Yes

115 LOPEZ PascalIRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

lopez@unice.fr 04 93 37 77 80 Yes

116 LOTTE RomainC3M - Centre Méditerranéen de Médecine Moléculaire

Master Student

lotte.r@chu-nice.fr 04 89 06 42 62 Yes

117 LOUBIERE CamilleC3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

loubiere@unice.fr 04 89 06 42 29 Yes poster 3

118 LOUDHAIEF Rihab iBV - Institut de Biologie Valrose PhD student

Rihab.Loudhaief@sophia.inra.fr 06 23 50 37 85 No poster 2

119 LOUET Jean-Francois C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

jflouet@unice.fr 06 20 73 86 01 Yes poster 4

120 LUKIANETS Nikita iBV - Institut de Biologie Valrose PhD student

nikita.lukianets@unice.fr 07 52 62 60 26 Yes

121 LUTON Frédéric IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

luton@ipmc.cnrs.fr 04 93 95 77 70 Yes

122 MAGNALDO ThierryIRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

Thierry.Magnaldo@unice.fr 04 93 37 76 70 Yes Organizer

123 MAGRINELLI Elia iBV - Institut de Biologie Valrose PhD student

elia.magrinelli@gmail.com 04 92 07 64 20 Yes poster 2

124 MALLAVIALLE AudeC3M - Centre Méditerranéen de Médecine Moléculaire

Engineer mallavia@unice.fr 04 89 06 43 13 Yes

125 MARI BernardIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

mari@unice.fr 04 93 957 791 Yes

126 MARTIN StéphaneIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

Martin@ipmc.cnrs.fr 04 93 95 34 61 Yes Organizer

127 MARTIN Pauline iBV - Institut de Biologie Valrose PhD student

pauline.martin@unice.fr 06 21 80 49 99 Yes poster 4

128 MASSA Fabienne C3M - Centre Méditerranéen de Médecine Moléculaire

Post-doc fabienne.massa@unice.fr 04 89 06 42 29 Yes

129 MATUSEK Tamas iBV - Institut de Biologie Valrose Post-doc tmatusek@unice.fr 04 92 07 64 43 Yes poster 1

130 MAUROY Benjamin LJAD - Laboratoire JA DieudonnéResearcher / Lecturer

mauroy@unice.fr 04 92 07 62 10 No poster 5

131 MEDINA Clémence ISA - Institut Sophia Agrobiotech, INRAPhD student

clemence.medina@sophia.inra.fr

06 89 39 58 78 Yes

132 MEHLEN Patrick Research Cancer Center of Lyon Researcher / Lecturer

patrick.mehlen@lyon.unicancer.fr

04 78 78 28 70 NoInvited Keynote

Lecture talk 4

133 MESMIN BrunoIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Post-doc mesmin@ipmc.cnrs.fr 04 93 95 77 72 Yes poster 1

134 MONDRAGON-MARTINEZ LauraC3M - Centre Méditerranéen de Médecine Moléculaire

Post-doc laura.mondragon-martinez@unice.fr

04 89 06 43 01 Yes

135 MORATAL Claudine iBV - Institut de Biologie Valrose PhD student

cmoratal@unice.fr 04 93 37 70 38 Yes poster 2

136 MOTHE-SATNEY IsabelleC3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

satney@unice.fr 04 89 06 43 46 No

137 MOURGUES LucasC3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

lmourgues@unice.fr 04 89 06 43 18 No poster 4

138 MUNRO Patrick C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

munro@unice.fr 04 89 06 42 63 Yes

139 MUS-VETEAU Isabelle IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

mus-veteau@ipmc.cnrs.fr 04 93 95 77 51 Yes

140 NAESSENS Elodie ISA - Institut Sophia Agrobiotech, INRAPhD student

elodie.naessens@sophia.inra.fr 06 52 91 21 82 No

141 NAHON Jean-Louis IPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

nahonjl@ipmc.cnrs.fr 04 93 95 77 53 Yes Organizer

142 NAIMI MouradIRCAN - Institute for Research on Cancer and Aging, Nice

Clinician naimi@unice.fr 04 93 37 77 97 Yes

143 NAPOLITANO Tiziana iBV - Institut de Biologie Valrose PhD student

tiziana.napolitano@unice.fr 04 92 07 64 16 Yes

144 NOSELLI Stéphane iBV - Institut de Biologie Valrose Researcher / Lecturer

noselli@unice.fr 04 92 07 64 33 Yes Organizer

No. Last Name First Name Research institute or laboratory Function Email Phone SIGNALIFE member special participant Presentation Axis

145 OBBA SandrineC3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

sobba@unice.fr 04 89 06 43 06 Yes

146 PANABIERES Franck ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

franck.panabieres@sophia.inra.fr

04 92 38 65 18 Yes

147 PASCO Matthieu ISA - Institut Sophia Agrobiotech, INRA Post-doc pasco@unice.fr 06 88 15 26 74 No

148 PASTOR Faustine C3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

fpastor@unice.fr 06 75 65 66 89 Yes

149 PERALDI Pascal iBV - Institut de Biologie Valrose Researcher / Lecturer

peraldi@unice.fr 04 93 37 77 04 Yes

150PERFUS-BARBEOCH (ZURLETTO)

Laetitia ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

zurletto@sophia.inra.fr 04 92 38 64 94 YesSIGNALIFE Keynote

Lecture talk 3

151 PEYRE Ludovic ISA - Institut Sophia Agrobiotech, INRA Post-doc ludovic.peyre@sophia.inra.fr 04 92 38 64 48 No

152 PICCO Vincent CSM - Centre Scientifique de Monaco Researcher / Lecturer

vpicco@centrescientifique.mc +377 97 77 44 15 No

153 PLANTIVAUX Amandine Freelance consultant

plantivaux@yahoo.fr 06 47 02 35 23 No

154 POIRIE Marylène ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

poirie@sophia.inra.fr 04 92 38 64 09 Yes

155 POTTIER Anaïs C3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

apottier@unice.fr 04 89 06 43 13 Yes poster 4

156 PRATX Loris ISA - Institut Sophia Agrobiotech, INRAPhD student

lpratx@gmail.com 04 92 38 64 94 Yes poster 3

157 PRESSE FrançoiseIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

presse@ipmc.cnrs.fr 04 93 95 77 50 Yes

158 PROD'HOMME Virginie C3M - Centre Méditerranéen de Médecine Moléculaire

Post-doc prodhomme@unice.fr 04 89 06 43 13 Yes poster 4

159 QUENTIN Michaël ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

michael.quentin@sophia.inra.fr 04 92 38 64 95 Yes

160 RASSOULZADEGAN Minoo iBV - Institut de Biologie Valrose Researcher / Lecturer

minoo@unice.fr 04 92 07 64 12 Yes

161 RAVAUD Christophe iBV - Institut de Biologie Valrose PhD student

chris.ravaud@orange.fr 06 76 95 00 63 Yes

162 REINGOLD Victoria ISA - Institut Sophia Agrobiotech, INRAPhD student

vickire@gmail.com 06 08 05 95 65 Yes poster 2

163 REPETTO EmanuelaC3M - Centre Méditerranéen de Médecine Moléculaire

Post-doc erepetto@unice.fr 04 89 06 42 56 Yes poster 4

164 REVEL Johana SYMAR - Symbiose MarinePhD student

johana.revel@unice.fr 06 21 64 56 83 No

165 RIBEIRO Carolina W ISA - Institut Sophia Agrobiotech, INRA Post-doc xuwerner@gmail.com 06 51 47 60 52 Yes poster 3

166 RICCI Jean-Ehrland C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

ricci@unice.fr 04 89 06 43 04 Yes

167 RICCI Lorenzo LBDV - Laboratoire de Biologie du développement de Villefranche

PhD student

lricci@obs-vlfr.fr 06 13 74 57 81 No

168 ROBICHON Alain ISA - Institut Sophia Agrobiotech, INRAResearcher / Lecturer

alain.robichon@sophia.inra.fr 06 71 71 23 51 Yes

169 ROUANET SophieIRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

srouanet@unice.fr 06 29 85 03 84 Yes poster 4

170 ROUMENGOUS Solange iBV - Institut de Biologie Valrose PhD student

solange.roumengous@unice.fr 06 13 04 40 97 Yes

171 ROVERE CaroleIPMC - Institut de Pharmacologie Moléculaire et Cellulaire

Researcher / Lecturer

rovere@ipmc.cnrs.fr 04 93 95 77 41 Yes

172 RUBIO-PATINO CAMILAC3M - Centre Méditerranéen de Médecine Moléculaire

Post-doc crubiopatino@unice.fr 06 52 34 55 11 Yes

173 RUEL Laurent iBV - Institut de Biologie Valrose Researcher / Lecturer

ruel@unice.fr 04 92 07 64 58 Yes

174 RUGGIERO Antonella LBDV - Laboratoire de Biologie du développement de Villefranche

PhD student

ruggiero@obs-vlfr.fr 04 93 76 39 79 No

175 SABOURAULT Cécile SYMAR - Symbiose MarineResearcher / Lecturer

Cecile.Sabourault@unice.fr 04 92 07 68 95 No

176 SAUCET Simon ISA - Institut Sophia Agrobiotech, INRA Post-doc Simon.Saucet@sophia.inra.fr 06 66 22 47 77 No

177 SAVASTA Marc INSERM - Regional Delegation PACAC Researcher / Lecturer

marc.savasta@inserm.fr 04 91 82 70 39 No

178 SHARMA Priyanka iBV - Institut de Biologie Valrose PhD student

psharma@unice.fr 04 92 07 64 40 Yes

179 STUDER Michèle iBV - Institut de Biologie Valrose Researcher / Lecturer

michele.studer@unice.fr 04 92 07 64 19 Yes Organizer

180 TANTI Jean-François C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

tanti@unice.fr 04 89 06 42 37 Yes Organizer

181 TARTARE DECKERT SophieC3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

tartare@unice.fr 04 89 06 43 10 Yes

182 THEROND Pascal iBV - Institut de Biologie Valrose Researcher / Lecturer

therond@unice.fr 06 30 94 66 39 Yes

183 THOMSON Darren iBV - Institut de Biologie Valrose Post-doc Darren.THOMSON@unice.fr +44 79 80 40 56 54

Yes

184 TICHET Mélanie C3M - Centre Méditerranéen de Médecine Moléculaire

Post-doc tichet@unice.fr 04 89 06 43 13 Yes poster 4

185 TISSOT Floriane IRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

floriane.tissot@unice.fr 06 50 81 11 23 Yes

186 TOUZOT Audrey iBV - Institut de Biologie Valrose PhD student

atouzot@unice.fr 04 92 07 64 20 Yes

187 TRABUCCHI Michele C3M - Centre Méditerranéen de Médecine Moléculaire

Researcher / Lecturer

mtrabucchi@unice.fr 04 89 06 42 56 Yes

188 TRUONG Nhat My ISA - Institut Sophia Agrobiotech, INRAPhD student

nhat-my.truong@sophia.inra.fr 06 34 02 42 67 Yes

189 TURCHI Laurent iBV - Institut de Biologie Valrose Engineer turchi@unice.fr 04 92 07 64 74 Yes

190 VAN OBBEERGHEN Emmanuel IRCAN - Institute for Research on Cancer and Aging, Nice

Researcher / Lecturer

vanobbeg@unice.fr 04 93 37 77 85 YesSIGNALIFE keynote lecture/ Organizer

talk 2

191 VAN OBBERGHEN-SCHILLING Ellen iBV - Institut de Biologie Valrose Researcher / Lecturer

vanobber@unice.fr 04 92 07 64 30 Yes Organizer

No. Last Name First Name Research institute or laboratory Function Email Phone SIGNALIFE member special participant Presentation Axis

192 VIDAL Valérie iBV - Institut de Biologie Valrose Researcher / Lecturer

vvidal@unice.fr 04 92 07 64 73 Yes

193 VIEIRA Andhira iBV - Institut de Biologie Valrose PhD student

avieira@unice.fr 04 92 07 64 56 Yes poster 2

194 VIELLE Anne iBV - Institut de Biologie Valrose Engineer avielle@unice.fr 04 92 07 68 89 Yes

195 VILLA Elodie C3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

elodie.villa@unice.fr 06 70 79 39 04 Yes

196 VILLAGEOIS Phi iBV - Institut de Biologie Valrose Engineer villageo@unice.fr 04 93 37 76 65 Yes

197 VIOLLET SébastienIRCAN - Institute for Research on Cancer and Aging, Nice

PhD student

sebastien.viollet@unice.fr 06 42 75 27 85 Yes poster 2

198 VIROLLE Virginie iBV - Institut de Biologie Valrose Engineer vvirolle@unice.fr 04 92 07 68 02 Yes

199 WAKADE Rohan Sanjay iBV - Institut de Biologie Valrose PhD student

rohan.wakade@unice.fr 07 59 13 05 30 Yes

200 ZUBIOLO AlexisInria - Centre de Recherche Inria Sophia Antipolis - Méditerranée

PhD student

alexis.zubiolo@i3s.unice.fr 06 79 33 98 15 Yes poster 5

201 ZUNINO Barbara C3M - Centre Méditerranéen de Médecine Moléculaire

PhD student

zb909202@etu.unice.fr 04 89 06 43 03 Yes poster 3

85

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