S c i e n t i f i c D i r e c t o ry 2015 - 2019

S c i e n t i f i c D i r e c t o ry 2015 - 2019

Gustave Roussy was first created as the “Institut du Cancer” by Pr. Gustave Roussy in 1926 and gathers on its campus around 3,000 professionals, including 239 MD, whose missions are to treat cancer patients, to set up innovative therapies and to develop and spread the knowledge within medical and scientific communities.

The Institute is headed by Pr. Alexander Eggermont and its specificity is based on the integration between innovative healthcare and a top level research through a tight cooperation with the Université Paris-Sud and its Faculty of Medicine. In 2014, the Institute ensured 228,000 medical consultations and hosted 11,800 new patients, 26% of whom have benefited from an innovative therapy through the enrollment in one of the 369 ongoing clinical studies.

Since January 1st 2015, the Chevilly-Larue hospital (CHSP) has merged with Gustave Roussy; which increased the total number of hospital beds up to 435 and of outpatient units up to 102.

The Gustave Roussy research landscape now comprises 37 research teams (from basic science to translational biological research, from epidemiology and biostatistics to psycho-oncology and health economy), 14 clinical research teams each focused on one organ or pathology, a clinical research division which manages all the aspects of the clinical research (methodology, biostatistics, regulatory affairs, operations and pharmacovigilance), a hospital department dedicated to therapeutic innovations and early clinical trials as well as a 10 technology core facilities brought together within one administrative “Service Unit”. Research at Gustave Roussy is coordinated by Pr. Eric Solary.

In the last years, a global reflection has been initiated about the evolution of the technologies core facilities within Gustave Roussy. As far as genomics is concerned, Gustave Roussy has externalised the high-

throughput sequencing for the molecular medicine program (through a partnership with a biotech company, INTEGRAGEN, which installed and operates a “clinical sequencing unit” within the Institute), and proposes to merge its 2 genomics facilities (for clinical and basic research) within a unique facility that can share expertise, personnel and technology.

The robotised fluorescence videomicroscopic facility for high-throughput screening is now available and the creation of a “pharmacology Platform” for clinical and basic research is envisioned. Moreover, the management of the Tumour Bank (~150,000 tumor samples) is being profoundly modified to give a better access to tumour samples and to store biological samples upon prospective research programs.

The Molecular Medicine Program has been refined by new trial designs with the aim to answer the question of resistance to targeted therapies (i.e. MATCH-R) including sequential biopsies and xenografts.

The Gustave Roussy Immunotherapy Program (GRIP) has been initiated following the recruitment of clinical immunologist who is setting up immunotherapy clinical trials associated with translational research.

The onco-haematology program will be reinforced by the creation of the hospital haematology department which will give visibility and coherence to the haematology clinical activities and foster collaboration with Gustave Roussy research teams.

According to the SAB 2013 recommendations, several cross-program research projects are being developed (e.g linking immunology and DNA repair).

The development of the clinical research has been mainly focused on early phase clinical trials through the creation of the Drug Development department dedicated to therapeutic innovations and

Alexander EggermontDirector General

Eric SolaryDirector of Gustave Roussy Research

early clinical trials, the recruitment of a senior methodologist specialised in early phase trial and adaptive designs, and the coordination of the Institute’s industrial partnerships.

The present book introduces research groups and clinical committees currently operating in Gustave Roussy and the platforms they use. DNA repair, tumour immunology and molecular medicine are the three main axes of basis and translational research, with clinical research introducing new drugs and testing biomarkers.

Strengthening international partnerships

Internationally, Gustave Roussy is developing a program to promote its model of care, to train foreign professionals, and to improve access to cancer care for all patients through hospital projects abroad, which may be one-off or occur several times a year.

These have taken place in partner countries such as Kazakhstan, Kuwait and the United Arab Emirates.

On the research side, the Institute played a key role in the founding, in July 2014, of “Cancer Core Europe”, a European comprehensive cancer center consortium that involves 5 other Cancer Centres (DKFZ / NCT, VHIO, NKI, Cambridge Cancer Center, Karolinska Institute). Cancer Core Europe will make the bridge «bench-to-bedside and bedside-to-bench» and conduct next-generation clinical trials focused on proof-of-concept, companion, predictive and

resistance monitoring, biomarkers.

Several working groups have been set up, among which the “IT/ Data Sharing working group” will develop a common software platform to integrate all patient data that federates the databases from each of the centres. In less than a year, the consortium has already been successful in two European calls: TRANSCAN and EIT Health.

Gustave Roussy has drawn its future roadmap through its Development Program 2015-2020. Resulting from several months of work by all the professionals at the Institute, it provides a framework, based on existing foundations, for an innovative Comprehensive Cancer Centre. Within this program, the three main actions for research are: (i) the creation of clinician-researchers positions (MD/PhD or PharmaD/PhD) whose workload will be mainly focused on ambitious exploratory and/or translational research projects; (ii) the construction of a preclinical cancer research facility (PRECAN); (iii) the creation in 2020 of a renewed Research Centre endorsed by the National Institutions (including basic, translational and clinical research).

This last objective is highly strategic. The Institute aims at building on an integrated, first-class, innovative research based on highly-talented scientists, clinicians and staff members. After evaluating the potential of candidate research team leaders, a proposal for a future research strategy and organisation of the Research Centre will be discussed, in a very open system of exchange.

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RESEARCH KEY NUMBERS fRoM 2012-2014

A growing part of IF>20 within the total number of publications

Number of PublicatioNs iN Peer review jourNal

Number of PatieNts iNcluded iN cliNical studies by sPoNsor

research workforce (full time equivaleNt - fte)113 Phd studeNts iNcludiNg 41% of NoN-freNch Phd studeNts

coNsolidated budget (m€)

research workforce

key Numbers 2014

124 1422013 20142012

0

400

800

1200

200

600

1000

1400

180

Academic (except GR)

Industrials

Gustave Roussy

Total

France

Europe

Russia

Asia

India

Latin America

North Africa

Middle East

Research Teams and technologicals facilities (Others)

Clinical Research (GR)

Research Teams and Technological facilities (GR)

Total Research Manpower

2 813

3 690

3 308

2013 20142012

0

1 000

1 500

2 000

3 000

3 500

4 000

500

2 500

2013 20142012

0

40

60

80

20

100

2013 20142012

879,5 972,4822,85

0

400

600

800

200

1 000

The consolidated budget corresponds to ALL research expenses for any research activity on Gustave Roussy Campus, given that these expenses can be incurred by Gustave Roussy or not (i.e. salaries of the academic positions, grants that are managed in other institutions, etc.)

70,1

90,1 85,5

972 Full Time Equivalent (FTE) assigned to the Research Division, including • 656 FTE employed by Gustave Roussy in the Technological facilities, Clinical Research and Research Teams, • 316 FTE not employed by Gustave Roussy (Inserm, CNRS, Paris-Saclay University, others) in the Research

Teams and Technological Facilities

67

46

41

11

1

19

PatieNts iNcluded iN cliNical studies• 3 308 patients included in clinical studies including 434 patients in early phase clinical trials• 331 ongoing clinical trial including 86 early phase clinical trials• 30 % of Gustave Roussy’s new patients included in a clinical study

PublicatioNs iN Peer review jourNal• 1150 publications in peer review journalsincluding 180 in journals whose IF>10

Pub IF 10

UMR 981 INSERM: PREdIctIvE bIoMARkERS ANd NEw MolEcUlAR StRAtEgIES FoR cANcER thERAPyFabrice André P. 17

UMR 1170 INSERM: NoRMAl ANd MAlIgNANt hAEMAtoPoIESISOlivier Bernard P. 19

genetic and Epigenetic control of normal and malignant haematopoiesis (AtIP-AvENIR)Camille Lobry P. 20

genetic and modelling of paediatric leukaemiaThomas Mercher P. 21

Endocytosis, cytoskeleton and cell migration (AtIP-AvENIR)Guillaume Montagnac P. 22

Early steps of haematopoietic transformation Virginie Penard Lacronique, Olivier Bernard P. 23

haematopoietic stem cells to the differentiation of megakaryocytesHana Raslova P. 24

From haematopoietic stem cell to myelomonocytic differentiationEric Solary, Françoise Porteu P. 25

UMR 8081 cNRS: MAgNEtIc RESoNANcE IMAgINg ANd MUltI-MEdIcAl tERMS (IR4M)Luc Darrasse

Multimodal imaging in oncologyNathalie Lassau P. 27

UMR 1030 INSERM: MolEcUlAR RAdIothERAPyEric Deutsch P. 29

tumour Response to Radiation therapyEric Deutsch, Nazanine Modjtahedi P. 30

cell death and Aging teamJean-Luc Perfettini P. 31

UMR 1018 INSERM - cENtRE FoR RESEARch IN EPIdEMIology ANd PoPUlAtIoN hEAlth (cESP)Bruno Falissard P. 32

Scientific Directory 2015 - 2019

1. RESEARch tEAMS lifestyle, genes and health: integrative trans-generational epidemiologyMarie-Christine Boutron-Ruault P. 33

Methodology and clinical Epidemiology in Molecular oncologyStefan Michiels P. 34

Radiation Epidemiology, clinical Epidemiology of cancer and survivalFlorent de Vathaire P. 35

UMR 9196 cNRS: MolEcUlAR PhySIology ANd PAthology oF INFEctIoUS ANd ENdogENoUS REtRovIRUSESThierry Heidmann P. 37

UMR 8200 cNRS: gENEtIc StAbIlIty ANd oNcogENESIS Patricia Kannouche P. 38

cell division and genomic stabilityOlivier Gavet P. 39

tlS Polymerases and genome Plasticity Patricia Kannouche, Said Aoufouchi P. 40

Recombination, Repair, RoS and cancerBernard Lopez, Corinne Dupuy P. 41

Repair of double strand breaks and genome integrity (AtIP-AvENIR)Gerard Mazon P. 42

Replication stress, genomic instability and mitosis (ERc Starting grant)Valeria Naim P. 43

dNA repair Syndromes Filippo Rosselli P. 44

dNA repairMurat Saparbaev P. 45

UMR 1138 INSERM: APoPtoSIS, cANcER & IMMUNItyGuido Kroemer P. 47

UMR 1186 INSERM: INtEgRAtIvE tUMoUR IMMUNology ANd gENEtIc oNcologyFathia Mami-Chouaib P. 49

oncogenesis and tumour progression in melanoma (AtIP-AvENIR)Mehdi Khaled P. 50Integrative tumour Immunology and genetic oncologyFathia Mami-Chouaib P. 51

EA7348 EhESP – EcolE dES hAUtES EtUdES EN SANté PUblIqUE

Management of health organisationEtienne Minvielle P. 53

UMR 8203 cNRS: vEctoRology ANd thERAPEUtIc ANtIcANcERLluis Mir P. 55

New anticancer therapies Liliane Massade, Jacques Grill P. 56

vectorology nucleic acids and anticancer drugsLuis Mir, Karim Benihoud P. 57

UMR 8126 cNRS: SIgNAllINg, NUclEI ANd INNovAtIoN IN oNcologyJoëlle Wiels P. 58

Microenvironment, exosomes and microRNAs in solid tumours Pierre Busson P. 59

Intracellular traffic, macromolecular complexes and cancerSvetlana Dokudovskaya P. 60

collective invasion (AtIP-AvENIR)Fanny Jaulin P. 61

Maintenance of genomes and Molecular MicroscopyÉric Le Cam P. 62

Proteomics and Epigenetics Vasily Ogryzko P. 63

Nuclear organisation and pathological modelsYegor Vassetzky / Marc Lipinski P. 64

oncogenesis and resistance to apoptosis in b lymphomaJoëlle Wiels P. 65

UMR 1015 INSERM: tUMoUR IMMUNology ANd IMMUNothERAPy oF cANcERLaurence Zitvogel P. 67

Role of RNA translation in antigen presentationSébastien Apcher P. 68

Regulation of the effector anti-tumour function by dendritic cells and exosomes: towards the designationLaurence Zitvogel P. 69

2. clINIcAl RESEARch

clINIcAl RESEARch tEAMS P. 72

genito-Urinary cancerLaurence Albiges P. 73

Endocrine tumoursEric Baudin P. 74

thoracic cancerBenjamin Besse P. 75

oncogeneticsOlivier Caron P. 76

SarcomasAxel Le Cesne P. 77

breast cancerSuzette Delaloge P. 78

brain tumourFrédéric Dhermain P. 79

Paediatric malignanciesJacques Grill P. 80

gastro Intestinal cancerDavid Malka P. 81

gynecologic cancerPatricia Pautier P. 82

haematological malignanciesVincent Ribrag P. 83

dermatologyCaroline Robert P. 84

head and Neck cancerStéphane Temam P. 85

PSycho-oNcology UNItSarah Dauchy P. 86

clINIcAl RESEARch dIvISIoNGilles Vassal P. 89

biostatistics and epidemiology unit (SbE)Ellen Benhamou P. 90

operations Unit (SoRc)Valérie Dejean P. 91

Pharmacovigilance Unit (UFPv)Salim Laghouati P. 92

clinical trial Sponsoring Unit (SPEc)Delphine Vuillier-Legoff P. 93

EARly dRUg dEvEloPMENt dEPARtMENt (dItEP)Jean-Charles Soria P. 94

INdUStRIAl PARtNERShIPS cooRdINAtIoN coMMIttEE (ccPI)Eric Angevin P. 95

3. coRE FAcIlItIES

cNRS UMS3655 - INSERM US23: MolEcUlAR ANAlySIS, ModEllINg ANd IMAgINg oF cANcER dISEASEJean-Yves Scoazec P. 98Immune Monitoring laboratory in oncology: Nathalie Chaput P. 99genomicsNathalie Droin, Ludovic Lacroix P. 100circulating tumour cells Françoise Farace P. 101bioinformatics: Daniel Gautheret P. 102Preclinical evaluation platform Patrick Gonin P. 103Metabolomics Guido Kroemer P. 104Imaging and cytometry platform Corinne Laplace-Builhé P. 105Proteomics Vasily Ogryzko P. 106biological resource centre: Jean-Yves Scoazec P. 107histopathology Jean-Yves Scoazec P. 108

UMR 1138 INSERM - dRUg ScREENINg PlAtFoRM (PAcRI)Guido Kroemer P. 109

r e S e a rc h t e a m S

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UMR 981 INSERM: PREdIctIvE bIoMaRkERS aNd NEw MolEcUlaR StRatEgIES foR caNcER thERaPyResearch Unit director: Fabrice AndréSingle team Unit

kEywoRdSMolecular predictor, clinical trial, biomarker, translational research, high throughput biology, bioinformatics, therapeutic target.

eIF4F is a nexus of resistance to anti BRAF and anti-MEK cancer therapies. Boussemart L, Malka-Mahieu H, Girault I, Allard D, Hemmingsson O, Tomasic G, Thomas M, Basmadjian C, Ribeiro N, Thuaud F, Mateus C, Routier E, Kamsu-Kom N, Agoussi S, Eggermont AM, Désaubry L, Robert C, Vagner S. Nature 2014 Sep 4;513(7516):105-9.

Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER). André F, Bachelot T, Commo F, Campone M, Arnedos M, Dieras V, Lacroix-Triki M, Lacroix L, Cohen P, Gentien D, Adélaide J, Dalenc F, Goncalves A, Levy C, Ferrero JM, Bonneterre J, Lefeuvre C, Jimenez M, Filleron T, Bonnefoi H. Lancet Oncol. 2014 Mar;15(3):267-74.

ERCC1 isoform expression and DNA repair in non-small-cell lung cancer. Friboulet L, Olaussen KA, Pignon JP, Shepherd FA, Tsao MS, Graziano S, Kratzke R, Douillard JY, Seymour L, Pirker R, Filipits M, André F, Solary E, Ponsonnailles F, Robin A, Stoclin A,

Dorvault N, Commo F, Adam J, Vanhecke E, Saulnier P, Thomale J, Le Chevalier T, Dunant A, Rousseau V, Le Teuff G, Brambilla E, Soria JC. N Engl J Med. 2013 Mar 21;368(12):1101-10.

Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer.Vignot S, Frampton GM, Soria JC, Yelensky R, Commo F, Brambilla C, Palmer G, Moro-Sibilot D, Ross JS, Cronin MT, André F, Stephens PJ, Lazar V, Miller VA, Brambilla E. J Clin Oncol. 2013 Jun 10;31(17):2167-72.

Reversing resistance to vascular-disrupting agents by blocking late mobilization of circulating endothelial progenitor cells.Taylor M, Billiot F, Marty V, Rouffiac V, Cohen P, Tournay E, Opolon P, Louache F, Vassal G, Laplace-Builhé C, Vielh P, Soria JC, Farace F. Cancer Discov. 2012 May;2(5):434-49.

ToP 5 PUBLICATIoNS

SUMMaRy of thE RESEaRch toPIcS:The aim of the Unit is the identification and validation of new therapeutic targets and molecular predictors in oncology. The Unit’s work is based on the principle that high-throughput molecular characterisation can lead to the identification of therapeutic targets. The mission is to transfer the molecular knowledge to clinical practice, and use patient samples as source of hypotheses for research.

the following elements underlie the principles of the Unit:a. One of the objectives is the set-up of clinical trials which test the biomarkers;b. The Unit can either pilot projects or support other units performing fundamental research for the transfer of their concepts;c. The development of technologies and bioinformatic tools for translational research is part of the objectives of the Unit;d. Every project must be co-piloted by a researcher and a clinician.

• 7 patents • 13 ongoing industrial partnerships

dEtaIlS: gustave Roussy, Inserm UMR 981, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 56 30e-mail: Fabrice.ANdRE@gustaveroussy.fr http://u981.medecinemoleculaire.org/

tEaM MEMbERS:- Permanent researchers: 4 Inserm/CNRS - Faculty members: 2 Associate Professors (MCU)- Technical staff: 6- Non-permanent researchers: 7 post-docs- PhD students: 14 (2010-2014)- Others: 3 University Professor-Hospital Practitioners (>20% of time in the Unit) and 6 interns

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UMR 1170 INSERM: NoRMal aNd MalIgNaNt haEMatoPoIESISResearch Unit director: olivier bernard

gENEtIc ANd EPIgENEtIc coNtRol oF NoRMAl ANd MAlIgNANt hAEMAtoPoIESIS (AtIP-AvENIR)Camille Lobry

gENEtIc ANd ModEllINg oF PAEdIAtRIc lEUkAEMIAThomas Mercher

ENdocytoSIS cytoSkElEtoN ANd cEll MIgRAtIoN(AtIP-AvENIR)Guillaume Montagnac

EARly StEPS oF hAEMAtoPoIEtIc tRANSFoRMAtIoNVirginie Penard Lacronique, Olivier Bernard

hAEMAtoPoIEtIc StEM cEllS to thE dIFFERENtIAtIoN oF MEgAkARyocytESHana Raslova

FRoM hAEMAtoPoIEtIc StEM cEll to MyEloMoNocytIc dIFFERENtIAtIoNEric Solary, Françoise Porteu

2120

gENEtIc aNd EPIgENEtIc coNtRol of NoRMal aNd MalIgNaNt haEMatoPoIEtIc (atIP-avENIR)team leader: camille lobry

kEywoRdSleukaemia, epigenetic, stem cells, lncRNA, Notch

SRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognition.Kim E, Ilagan JO, Liang Y, Daubner GM, Lee SC, Ramakrishnan A, Li Y, Chung YR, Micol JB, Murphy ME, Cho H, Kim MK, Zebari AS, Aumann S, Park CY, Buonamici S, Smith PG, Deeg HJ, Lobry C, Aifantis I, Modis Y, Allain FH, Halene S, Bradley RK, Abdel-Wahab O.Cancer Cell. 2015 May 11;27(5):617-30.

TET1 is a tumor suppressor of hematopoietic malignancy.Cimmino L, Dawlaty MM, Ndiaye-Lobry D, Yap YS, Bakogianni S, Yu Y, Bhattacharyya S, Shaknovich R, Geng H, Lobry C, Mullenders J, King B, Trimarchi T, Aranda-Orgilles B, Liu C, Shen S, Verma AK, Jaenisch R, Aifantis I.Nat Immunol. 2015 Jun;16(6):653-62.

STAT3 supports experimental K-RasG12D-induced murine myeloproliferative neoplasms dependent on serine phosphorylation.Gough DJ, Marié IJ, Lobry C, Aifantis I, Levy DE.Blood. 2014 Oct 2;124(14):2252-61.

Notch signaling: switching an oncogene to a tumor suppressor.Lobry C, Oh P, Mansour MR, Look AT, Aifantis I.Blood. 2014 Apr 17;123(16):2451-9.

In vivo mapping of notch pathway activity in normal and stress hematopoiesis.Oh P, Lobry C, Gao J, Tikhonova A, Loizou E, Manent J, van Handel B, Ibrahim S, Greve J, Mikkola H, Artavanis-Tsakonas S, Aifantis I.Cell Stem Cell. 2013 Aug 1;13(2):190-204

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, Inserm UMR 1170, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 e-mail: camille.lobRy@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 1 Inserm- Technical staff: 1 Gustave Roussy- Non-permanent researchers: 1 Inserm

SUMMaRy of thE RESEaRch toPIcS:The maintenance of haematopoietic stem cells (HSC) is a tightly regulated process by transcription factors that control their self-renewal and commitment to differentiated blod lineages. A disruption of this process can lead to cell transformation and leukaemogenesis like Acute Myeloid Leukemia (AML). We focused our studies on the role of Notch in early stages of normal haematopoietic and in leukaemia transformation. Our work suggests that Notch signalling acts as a tumour suppressor in the AML and agonist molecules of this pathway could be used in targeted therapy.

The human transcriptome consists of not only coding RNAs for proteins but also non-coding RNAs. Among these non-coding RNAs, long non-coding RNAs (lncRNA) appear to play a critical role in controlling the expression of genes involved in the homeostasis of stem cells. However, their involvement in the control of HSC and their transformation into AML remains unexplored. Identifying and characterising such transcripts could allow design of novel targeted therapies for this disease.

Our research projects will focus on two main areas:-Molecular mechanisms of Notch function in early stages of haematopoiesis and leukaemic transformation to AML.-Analysis of the role of long non-coding RNA in the maintenance of haematopoietic stem cells, their differentiation and leukemic transformation.

gENEtIc aNd ModEllINg of PaEdIatRIc lEUkaEMIateam leader: thomas Mercher

kEywoRdShaematology; Oncology; paediatric leukaemia; Genetic studies; Fusion oncogenes; Transcription factors; Functional modelling; Preclinical studies

STAT3 mutations identified in human hematologic neoplasms induce myeloid malignancies in a mouse bone marrow transplantation model.Couronné L, Scourzic L, Pilati C, Della Valle V, Duffourd Y, Solary E, Vainchenker W, Merlio JP, Beylot-Barry M, Damm F, Stern MH, Gaulard P, Lamant L, Delabesse E, Merle-Beral H, Nguyen-Khac F, Fontenay M, Tilly H, Bastard C, Zucman-Rossi J, Bernard OA, Mercher T.Haematologica. 2013 Jul 19. PubMed PMID: 23872306.

Ikaros inhibits megakaryopoiesis through functional interaction with GATA-1 and NOTCH signaling.Malinge S, Thiollier C, Chlon TM, Doré LC, Diebold L, Bluteau O, Mabialah V, Vainchenker W, Dessen P, Winandy S, Mercher T*, Crispino JD*.Blood. 2013 Jan 18. PMID: 23335373. *Co-corresponding authorsComments: Maillard I, Blood. 2013 Mar 28;121(13):2376-7. PubMed PMID: 23538229.

Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models.Thiollier C, Lopez CK, Gerby B, Ignacimouttou C, Poglio S, Duffourd Y, Guégan J, Rivera-Munoz P, Bluteau O, Mabialah V, Diop M, Wen Q, Petit A, Bauchet AL, Reinhardt D, Bornhauser B,

Gautheret D, Lecluse Y, Landman-Parker J, Radford I, Vainchenker W, Dastugue N, de Botton S, Dessen P, Bourquin JP, Crispino JD, Ballerini P, Bernard OA, Pflumio F, Mercher T.J Exp Med. 2012 Oct 22;209(11):2017-31. doi: 10.1084/jem.20121343.

TET2 Inactivation Results in Pleiotropic Hematopoietic Abnormalities in Mouse and Is a Recurrent Event during Human Lymphomagenesis. Quivoron C, Couronné L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, Do Cruzeiro M, Delhommeau F, Arnulf B, Stern MH, Godley L, Opolon P, Tilly H, Solary E, Duffourd Y, Dessen P, Merle-Beral H, Nguyen-Khac F, Fontenay M, Vainchenker W, Bastard C*, Mercher T*, Bernard OA*. Cancer Cell. 2011 Jul 12;20(1):25-38. PubMed PMID: 21723201. * Co-senior authors

Crosstalk between Notch and AKT signaling during murine megakaryocyte lineage specification.Cornejo MG, Mabialah V, Sykes SM, Khandan T, Lo Celso C, Lopez C, Rivera-Muñoz P, Rameau P, Tothova Z, Aster JC, Depinho RA, Scadden DT, Gilliland DG, Mercher T.Blood. 2011 Jun 7. [Epub ahead of print] PubMed PMID: 21653327.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, Inserm UMR 1170, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 42 33e-mail: thomas.MERchER@Inserm.fr

tEaM MEMbERS:- Permanent researchers: 2 Inserm- Technical staff: 2 (CDD)- Non-permanent researchers: 1- PhD students: 3

• 1 ongoing industrial partnership

SUMMaRy of thE RESEaRch toPIcS:Paediatric cancers affect about 1/600 child and represent the second cause of death in western countries. The haematological malignancies account for approximately 45% of the paediatric cancers. Clinical features of these paediatric cancers suggest that they have different bases compared to the corresponding adult cancers.

The overall goal of our studies is to identify the precise molecular mechanisms of transformation and the bases for the exclusive association between several genetic alterations and pediatric cancers in order to develop novel therapeutic strategies. We primarily focus on paediatric leukaemia presenting recurrent chromosomal alterations, including acute megakaryoblastic leukaemia (characterised

by several fusion oncogenes involving transcription regulators) and acute lymphoblastic leukemia frequently associated with trisomy 21.

We identify the genetic landscape of leukaemia and perform functional analyses using cellular and preclinical in vivo models, including transgenic, patient-derived xenotransplantation and CRISPR-based models.

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ENdocytoSIS, cytoSkElEtoN aNd cEll MIgRatIoN (atIP-avENIR)team leader : guillaume Montagnac

kEywoRdS Cell Biology; Migration / invasion; endocytosis; cytoskeleton; imaging

Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling.Boissan M, Montagnac G, Shen Q, Griparic L, Guitton J, Romao M, Sauvonnet N, Lagache T, Lascu I, Raposo G, Desbourdes C, Schlattner U, Lacombe ML, Polo S, van der Bliek AM, Roux A, Chavrier P.Science. 2014 Jun 27;344(6191):1510-5.

αTAT1 catalyses microtubule acetylation at clathrin-coated pits.Montagnac G, Meas-Yedid V, Irondelle M, Castro-Castro A, Franco M, Shida T, Nachury MV, Benmerah A, Olivo-Marin JC, Chavrier P.Nature. 2013 Oct 24;502(7472):567-70.

Decoupling of activation and effector binding underlies ARF6 priming of fast endocytic recycling.Montagnac G, de Forges H, Smythe E, Gueudry C, Romao M, Salamero J, Chavrier P.Curr Biol. 2011 Apr 12;21(7):574-9.

Abscission accomplished by PtdIns(3)P.Montagnac G, Chavrier P.Nat Cell Biol. 2010 Apr;12(4):308-10.

ARF6 Interacts with JIP4 to control a motor switch mechanism regulating endosome traffic in cytokinesis.Montagnac, G., Sibarita, J.B., Loubery, S., Daviet, L., Romao, M., Raposo, G., and Chavrier, P.Curr Biol. 2009.19, 184-195.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, Inserm UMR 1170, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 56 16e-mail: guillaume.MoNtAgNAc@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 1 Inserm- Technical staff: 2 Gustave Roussy- Non-permanent researchers: 2 postdoc Inserm- PhD students: 1- Autres: 2 (Gustave Roussy)

SUMMaRy of thE RESEaRch toPIcS:Endocytosis is a fundamental process that allows the cell to completely renew its plasma membrane and to internalise as much as three times its own volume in approximately one hour. More importantly, endocytosis allows the internalisation of membrane receptors and their ligands and thereby controls vital cell functions such as plasma membrane homeostasis, cell nutrition and intracellular signalling. All these functions make endocytosis an essential player in virtually all cell processes including cell migration, cell division, autophagy and many others.

Our group focuses on the mechanisms underlying cancer cell migration as well as on fundamental aspects of endocytosis and microtubules dynamics that directly affect the capacity of the cell to migrate and survive.

More specifically, we develop projects aiming at analysing and understanding:-The role of clathrin-coated pits during cell migration.-The interplay between actin and microtubule cytoskeletons and clathrin-coated pits.-The dynamics of microtubule acetylation -The dynamics of endocytosis in vivo

We particularly study the connections between endocytosis and the cytoskeletons at different levels by using reconstituted in vitro systems, cell culture in 2D and 3D and intravital analyses. We use a multidisciplinary approach combining biochemistry, cell biology and biophysics in order to understand how the cytoskeleton and endocytosis team up to regulate the different steps of cell migration.

EaRly StEPS of haEMatoPoIEtIc tRaNSfoRMatIoNteam leaders: virginie Penard-lacronique, olivier bernard

kEywoRdSStem cell, TET2, IDH, Spi1/PU.1, RhoA, DNA methylation, splicing, epigenetic, differentiation, haematopoietic malignancies.

TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis.Quivoron C, Couronne L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, Do Cruzeiro M, Delhommeau F, Arnulf B, Stern MH, Godley L, Opolon P, Tilly H, Solary E, Duffourd Y, Dessen P, Merle-Beral H, Nguyen-Khac F, Fontenay M, Vainchenker W, Bastard C, Mercher T, Bernard OA. Cancer Cell 2011;20:25-38.

Acquired initiating mutations in early hematopoietic cells of CLL patients. Damm F, Mylonas E, Cosson A, Yoshida K, Della Valle V, Mouly E, Diop M, Scourzic L, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Kikushige Y, Davi F, Lambert J, Gautheret D, Merle-Beral H, Sutton L, Dessen P, Solary E, Akashi K, Vainchenker W, Mercher T, Droin N, Ogawa S, Nguyen-Khac F, Bernard OA. Cancer Discov 2014;4:1088-101.

Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation.

Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S, Yen KE. Science 2013 May 3;340(6132):622-6.

Spi-1/PU.1 activates transcription through clustered DNA occupancy in erythroleukemia. Ridinger-Saison M, Boeva V, Rimmelé P, Kulakovskiy I, Gallais I, Levavasseur B, Paccard C, Legoix-Né P, Morlé F, Nicolas A, Hupé P, Barillot E, Moreau-Gachelin F, Guillouf C. Nucleic Acids Res. 2012 Oct;40(18):8927-41

TET2 and DNMT3A Mutations in Human T-Cell Lymphoma. Couronne L, Bastard C, Bernard OA. N Engl J Med 2012;366:95-6.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, Inserm UMR 1170, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 42 33 / 52 40e-mail: olivier.bERNARd@gustaveroussy.fr ; e-mail: virginie.lAcRoNIqUE-PENARd@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 4- Faculty members: 4- Technical staff: 5- Non-permanent researchers: 4 Post-docs- PhD students: 5- Others: 2

SUMMaRy of thE RESEaRch toPIcS:The over all aim of our team is to identify the acquired mutations in the early step of haematopoietic transformation, understand the network of cooperating events underlying transformation and develop experimental models to allow functional investigations and serve as preclinical models.

Most of the adult haematological malignancies arise from a pre-leukaemic phase that involves an infra-clinic expansion of abnormal, mutated haematopoietic stem/progenitor cells. It has been shown that genetic lesions in genes encoding for transcription factors (such as RUNX1, Spi1/PU.1), mRNA splicing (SF3B1, U2AF35), DNA methylation (Ten-Eleven-Translocation 2 (TET2), DNA (cytosine-5)-methyltransferase 3A (DNMT3A)), intermediate metabolism (Isocitrate Dehydrogenase 1 and 2 (IDH1/2)) or chromatin structure (SMC1A) are founding mutations in human malignancies.

We are investigating the functional consequences of TET2, DNMT3A and IDH genetic lesions, that frequently predate the development of myeloid or lymphoid malignancies and are involved in epigenetic gene regulation. We are studying the consequences of alteration in Spi1/PU activity, a transcriptional factor of the ETS family, which in addition to transcriptional regulation, plays a role in the control of epigenetic and RNA splicing regulation. In addition, we are analysing the roles of the GTPase RhoA and its regulators (GEFs & GAPs) during normal haematopoietic cell division and studying how mutations in RhoA may cooperate with epigenetic factors for lymphocyte transformation.

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haEMatoPoIEtIc StEM cEllS to thE dIffERENtIatIoN of MEgakaRyocytESteam leader: hana Raslova

kEywoRdSMegakaryocyte, thrombopenia, thrombocytosis, MPL, JAK2, Calreticuline, ontogeny, RUNX1, ANRKD26, cytoskeleton, myelofibrosis, iPSC

Progress in understanding the diagnosis and molecular genetics of macrothrombocytopenias.Favier R, Raslova H.Br J Haematol. 2015 May 5.

Level of RUNX1 activity is critical for leukemic predisposition but not for thrombocytopenia.Antony-Debré I, Manchev VT, Balayn N, Bluteau D, Tomowiak C, Legrand C, Langlois T, Bawa O, Tosca L, Tachdjian G, Leheup B, Debili N, Plo I, Mills JA, French DL, Weiss MJ, Solary E, Favier R, Vainchenker W, Raslova H.Blood. 2015 Feb 5;125(6):930-40.

p19 INK4d controls hematopoietic stem cells in a cell-autonomous manner during genotoxic stress and through the microenvironment during aging.Hilpert M, Legrand C, Bluteau D, Balayn N, Betems A, Bluteau O, Villeval JL, Louache F, Gonin P, Debili N, Plo I, Vainchenker W, Gilles L, Raslova H.Stem Cell Reports. 2014 Dec 9;3(6):1085-102.

A new form of macrothrombocytopenia induced by a germ-line mutation in the PRKACG gene.Manchev VT, Hilpert M, Berrou E, Elaib Z, Aouba A, Boukour S, Souquere S, Pierron G, Rameau P, Andrews R, Lanza F, Bobe R, Vainchenker W, Rosa JP, Bryckaert M, Debili N, Favier R, Raslova H.Blood. 2014 Oct 16;124(16):2554-63.

Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding.Canault M, Ghalloussi D, Grosdidier C, Guinier M, Perret C, Chelghoum N, Germain M, Raslova H, Peiretti F, Morange PE, Saut N, Pillois X, Nurden AT, Cambien F, Pierres A, van den Berg TK, Kuijpers TW, Alessi MC, Tregouet DA.J Exp Med. 2014 Jun 30;211(7):1349-62.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, Inserm UMR 1170, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 46 71e-mail: hana.RASlovA@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 4 Inserm, 2 CNRS- Faculty members: 1, Paris 6- Technical staff: 1 APHP, 1 Inserm / 1 (CDD) Gustave Roussy, 1 Inserm, 1 INTS- Non-permanent researchers: 3 Post-docs Inserm, 1 Post-doc Gustave Roussy, 1 INTS)- PhD students : 16 (dont 2 en cotutelle)- Others: 2 (PH) AP-HP

SUMMaRy of thE RESEaRch toPIcS:The team N°2 works principally on normal and pathological megakaryopoiesis. On normal megakaryopoiesis, our objectives are to better understand the ontogenetic changes, the role of some transcription factors, the epigenetic changes and the processes of polyploidisation and platelet formation. The applications are: i) understanding of platelet toxicity of some drugs; ii) the development of techniques to produce platelets in vitro. On pathological megakaryopoiesis, we studied hereditary diseases including thrombocytopenias (ex. those associated with mutations in RUNX1 (FPD/AML) and ANKRD26 (THC2) and thrombocytosis secondary to

mutations in MPL. Their precise mechanisms are studied in different cell models including iPSC. Myeloproliferative neoplasms (NMP) are the more important malignancies studied.

The work is based on the modelling of mutations, especially JAK2V6217F and calreticulin in various cell models and in vivo in mice to understand the mechanisms of transformation and how to target them. Finally the team is working on predisposition to malignancies characterisedby mutations in RUNX1, ANKRD26 and by duplication of a new susceptibility locus for NPM.

• 4 patents • 3 ongoing industrial partnerships

fRoM haEMatoPoIEtIc StEM cEll to MyEloMoNocytIc dIffERENtIatIoN team leaders: Eric Solary, Françoise Porteu

kEywoRdSHaematopoietic stem and progenitor cells, Hematopoietic niche, Monocytic lineage, cytokine receptors, myelomonocytic leukaemias

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts.Paggetti J, Haderk F, Seiffert M, Janji B, Distler U, Ammerlaan W, Kim YJ, Adam J, Lichter P, Solary E, Berchem G, Moussay E.Blood. 2015 Jun 22. pii: blood-2014-12-618025.

Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia.Selimoglu-Buet D, Wagner-Ballon O, Saada V, Bardet V, Itzykson R, Bencheikh L, Morabito M, Met E, Debord C, Benayoun E, Nloga AM, Fenaux P, Braun T, Willekens C, Quesnel B, Adès L, Fontenay M, Rameau P, Droin N, Koscielny S, Solary E; Groupe Francophone des Myélodysplasies.Blood. 2015 Jun 4;125(23):3618-26.

Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression.

Uzan B, Poglio S, Gerby B, Wu CL, Gross J, Armstrong F, Calvo J, Cahu X, Deswarte C, Dumont F, Passaro D, Besnard-Guérin C, Leblanc T, Baruchel A, Landman-Parker J, Ballerini P, Baud V, Ghysdael J, Baleydier F, Porteu F, Pflumio F.EMBO Mol Med. 2014 Apr 28;6(6):821-34. Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1.de Laval B, Pawlikowska P, Barbieri D, Besnard-Guerin C, Cico A, Kumar R, Gaudry M, Baud V, Porteu F.Blood. 2014 Jan 23;123(4):509-19.

Thrombopoietin-increased DNA-PK-dependent DNA repair limits hematopoietic stem and progenitor cell mutagenesis in response to DNA damage.de Laval B, Pawlikowska P, Petit-Cocault L, Bilhou-Nabera C, Aubin-Houzelstein G, Souyri M, Pouzoulet F, Gaudry M, Porteu F.Cell Stem Cell. 2013 Jan 3;12(1):37-48

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, Inserm UMR 1170, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 42 33e-mail: Eric.SolARy@gustaveroussy.fr; e-mail: Francoise.PoRtEU@gustaveroussy.fr

tEaM MEMbERS:-Permanent researchers: 4 Inserm, 2 Inserm, 1 CNRS- Faculty members: 2 PUPH Paris Sud et Paris 6- Technical staff: 1 Inserm, 1 CNRS, 1 Inserm, 2 (sur contrats) - Non-permanent researchers: 2 post-doct- PhD students: 5

SUMMaRy of thE RESEaRch toPIcS:Haematopoietic stem cells (HSCs) in the bone marrow give rise to all lineages of blood cells in a carefully controlled equilibrium. An expansion of the myelomonocytic lineage is associated with inflammation and ageing. A clonal expansion can also be observed in response to some genetic and epigenetic alterations of stem or progenitor cells.

Chemo/cytokines and the bone marrow niche environment affect HSC genomic stability, lineage commitment, and cellular differentiation. The team explores the molecular mechanisms that drive myelomonocytic expansion in

response to acute or chronic stresses, either inflammatory or genotoxic, and in the context of clonal myelomonocytic leukaemia.

We explore the role of three receptors, CSF1-R, CXCR4, and MPL in HSC lineage commitment in steady-state and stress conditions. We also analyse the signalling pathways involved in terminal monocytic differentiation and polarisation. Finally, we dissect the pathogenesis of chronic and acute myelomonocytic leukaemias, using primary cells and various in vitro / in vivo models.

• 2 ongoing industrial partnerships

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UMR 8081 cNRS: MagNEtIc RESoNaNcE IMagINg aNd MUltI-MEdIcal tERMS (IR4M)Research Unit director: luc darrasse

MUltIModal IMagINg IN oNcologyteam leader: Nathalie lassau

kEywoRdSMultimodal imaging, contrast ultrasound, MRI, photonics, biomarker validation, Translational Research, tumor vasculature, tumour microenvironment

Molecular ultrasound imaging using contrast agents targeting endoglin, vascular endothelial growth factor receptor 2 and integrin.Leguerney I, Scoazec JY, Gadot N, Robin N, Pénault-Llorca F, Victorin S, Lassau N.Ultrasound Med Biol. 2015 Jan;41(1):197-207.

Dynamic contrast-enhanced ultrasound parametric maps to evaluate intratumoral vascularization.Pitre-Champagnat S, Leguerney I, Bosq J, Peronneau P, Kiessling F, Calmels L, Coulot J, Lassau N. Invest Radiol. 2015 Apr;50(4):212-7.

Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic therapy for solid tumors: the French multicenter support for innovative and expensive techniques study. Lassau N, Bonastre J, Kind M, Vilgrain V, Lacroix J, Cuinet M, Taieb S, Aziza R, Sarran A, Labbe-Devilliers C, Gallix B, Lucidarme O, Ptak Y, Rocher L, Caquot LM, Chagnon S, Marion D, Luciani A, Feutray S, Uzan-Augui J, Coiffier B, Benastou B, Koscielny S.Invest Radiol. 2014 Dec;49(12):794-800.

Assessing the response to targeted therapies in renal cell carcinoma: technical insights and practical considerations.Bex A, Fournier L, Lassau N, Mulders P, Nathan P, Oyen WJ, Powles T.Eur Urol. 2014 Apr;65(4):766-77. doi: 10.1016/j.eururo.2013.11.031. Epub 2013 Nov 28. Review.

Sorafenib plus dacarbazine in solid tumors: a phase I study with dynamic contrast-enhanced ultrasonography and genomic analysis of sequential tumor biopsy samples.Lazar V, Lassau N, Meurice G, Loriot Y, Peña C, Massard C, Robert C, Robert T, Le Berre MA, de Baere T, Dessen P, Soria JC, Armand JP.Invest New Drugs. 2014 Apr;32(2):312-22.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, cNRS UMR 8081, IR4M, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 60 14e-mail: Nathalie.lASSAU@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 2 CNRS, 1 Gustave Roussy- Faculty members: 1 PU-PH- Technical staff: 7 Gustave Roussy- PhD students: 3- Others : 4 (doctors)

SUMMaRy of thE RESEaRch toPIcS:The information specifically provided by all medical imaging modalities (Ultrasound, CT Scanner, MRI, PET) are many of them complementary. Consequently, a multimodal approach is essential to improve diagnosis in oncology. This translates mainly by advances in the functional characterisation of tumour and microenvironment, such as temporal resolution and dynamic studies, characterisation of physical/biological events, metabolic, cellular and molecular targeting.

In this context, the team «Multi-modal imaging in Oncology», composed of radiologists, researchers and engineers,

conducts translational research programs with a double objective:• Development of multimodal imaging tools for clinical & preclinical approaches in US; MRI and PET-MRI imaging.• Development of novel characterisation tools for imaging the tumour microenvironment in an integration of biology imaging approach.Moreover, the team has a preclinical ultrasound platform (Paris-Sud University, FLI) with 4 ultrasound scanners dedicated to research.

• 10 ongoing industrial partnerships

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UMR 1030 INSERM: MolEcUlaR RadIothERaPyResearch Unit director: Eric deutsch

tUMoUR RESPoNSE to RAdIAtIoN thERAPyEric Deutsch, Nazanine Modjtahedi

cEll dEAth ANd AgINg tEAMJean-Luc Perfettini

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tUMoUR RESPoNSE to RadIatIoN thERaPyteam leaders: Eric deutsch, Nazanine Modjtahedi

kEywoRdSImmunity, Metabolism, tumour microenvironment and Radiotherapy

Interaction between AIF and CHCHD4 Regulates Respiratory Chain Biogenesis.Hangen E, Féraud O, Lachkar S, Mou H, Doti N, Fimia GM, Lam NV, Zhu C, Godin I, Muller K, Chatzi A, Nuebel E, Ciccosanti F, Flamant S, Bénit P, Perfettini JL, Sauvat A, Bennaceur-Griscelli A, Ser-Le Roux K, Gonin P, Tokatlidis K, Rustin P, Piacentini M, Ruvo M, Blomgren K, Kroemer G, Modjtahedi N.Mol Cell. 2015 Jun 18;58(6):1001-14.

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer.Mondini M, Nizard M, Tran T, Mauge L, Loi M, Clémenson C, Dugue D, Maroun P, Louvet E, Adam J, Badoual C, Helley D, Dransart E, Johannes L, Vozenin MC, Perfettini JL, Tartour E, Deutsch E.Mol Cancer Ther. 2015 Jun;14(6):1336-45.

Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling.

Ko A, Kanehisa A, Martins I, Senovilla L, Chargari C, Dugue D, Mariño G, Kepp O, Michaud M, Perfettini JL, Kroemer G, Deutsch E. Cell Death Differ. 2014 Jan;21(1):92-9.

IGF-1R targeting increases the antitumor effects of DNA-damaging agents in SCLC model: an opportunity to increase the efficacy of standard therapy. Ferté C, Loriot Y, Clémenson C, Commo F, Gombos A, Bibault JE, Fumagalli I,Hamama S, Auger N, Lahon B, Chargari C, Calderaro J, Soria JC, Deutsch E. Mol Cancer Ther.2013 Jul;12(7):1213-22

Radiosensitization by a novel Bcl-2 and Bcl-XL inhibitor S44563 in small-cell lung cancer. Loriot Y, Mordant P, Dugue D, Geneste O, Gombos A, Opolon P, Guegan J, Perfettini JL, Pierre A, Berthier LK, Kroemer G, Soria JC, Depil S, Deutsch E. Cell Death Dis. 2014

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, Inserm UMR 1030, 114, rue Edouard vaillant, 94805 villejuife-mail: Eric.dEUtSch@gustaveroussy.fr ; tel.: +33(0)1 42 11 49 98 e-mail: nazanine.ModJtAhEdI@gustaveroussy.frtel.: +33 1 42 11 54 91

tEaM MEMbERS:- Permanent researchers: 4 Gustave Roussy, 1 CNRS, 1 Inserm, 1 Paris-Sud- Technical staff: 1 Gustave Roussy, 1 Inserm- Non-permanent researchers: 3 post-doc- PhD students: 5

SUMMaRy of thE RESEaRch toPIcS:Recent advances in the understanding of genetic, molecular and cellular events have highlighted the fact that cancer is a complex disease of cell types and microenvironments and urged us to 1) develop an integrative research program in the field of radiation oncology in order to examine the complexity of tumour response to ionising radiation (IR) and 2) define novel targets and strategies exploitable in clinic and 3) develop the next generation radiation oncology. To reach our objectives, we are developing an ambitious basic research program that will be organised in 3 axes: (I) the immune axis, (II) the tumour microenvironment and metabolism axis and finally, (III) the technology axis. To

translate our research activities from bench to bedside, we have decided to (a) define and establish molecular and radiomics signatures of radioresistance, (b) identify cellular targets for radiosensitation in pre-clinical models, (c) take advantage of the metabolic reprogramming of radioresistant tumours for the proposal of new anti-cancer therapies, (d) classify human tumours with the help of identified molecular biomarkers, (e) develop diagnostic and prognostic tools and (f) define personalised therapeutic strategies that will combine radiation therapy

• 5 patents • 15 ongoing industrial partnerships

cEll dEath aNd agINg tEaMteam leader: Jean-luc Perfettini

kEywoRdSCell death, Senescence, Immunity, Radiotherapy

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer.Mondini M, Nizard M, Tran T, Mauge L, Loi M, Clémenson C, Dugue D, Maroun P, Louvet E, Adam J, Badoual C, Helley D, Dransart E, Johannes L, Vozenin MC, Perfettini JL, Tartour E, Deutsch E.Mol Cancer Ther. 2015 Jun;14(6):1336-45.

Entosis, a key player in cancer cell competition.Kroemer G, Perfettini JL.Cell Res. 2014 Nov;24(11):1280-1.

Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling.

Ko A, Kanehisa A, Martins I, Senovilla L, Chargari C, Dugue D, Mariño G, Kepp O, Michaud M, Perfettini JL, Kroemer G, Deutsch E. Cell Death Differ. 2014 Jan;21(1):92-9.

Editorial: Pannexin-1--the hidden gatekeeper for HIV-1.Paoletti A, Raza SQ, Voisin L, Law F, Caillet M, Martins I, Deutsch E, Perfettini JL.J Leukoc Biol. 2013 Sep;94(3):390-2.

Understanding the functions of tumor stroma in resistance to ionizing radiation: emerging targets for pharmacological modulation.Chargari C, Clemenson C, Martins I, Perfettini JL, Deutsch E.Drug Resist Updat. 2013 Feb-Apr;16(1-2):10-21.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, Inserm UMR 1030, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 65 73 / 54 24e-mail: Jean-luc.PERFEttINI@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 1 Inserm- Technical staff: 1 Inserm- Non-permanent researchers: 2 post-doc- PhD students: 4

SUMMaRy of thE RESEaRch toPIcS:Radiation therapy is a cornerstone of cancer management. After radiation exposure, cells may die through different modalities of death, ranging from apoptosis and senescence to autophagy or mitotic death. Despite these knowledge, the program(s) of death triggered in irradiated cells remain(s) elusive. For all these reasons, we decided (i) to further characterise the molecular basis of IR-induced cell death mechanisms, (ii) to develop preclinical mouse models to assess the impact of cell death types on the tumour microenvironment

and on the anti-tumour immune response, (iii) to determine whether the detection of cell death mechanisms could be a factor predictive of disease outcome or prognostic for radiotherapy efficiency and (iv) to identify new technological approaches that could modulate these cell death programs and enhance the efficiency of radiotherapy. Our research work will also address the involvement of cell death modalities on the “abscopal effect”, analyse cross-talks between micro-environmental cell types and evaluate the ability of new technologies to enhance (local or distant) radiation mediated immune responses.

• 4 patents • 6 ongoing industrial partnerships• 2 spin-off / startups / biotech

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UMR 1018 INSERM : cENtRE foR RESEaRch IN EPIdEMIology aNd PoPUlatIoN hEalth (cESP)Research Unit director: bruno Falissard

lIFEStylE, gENES ANd hEAlth: INtEgRAtIvE tRANS-gENERAtIoNAl EPIdEMIologyMarie-Christine Boutron-Ruault

MEthodology ANd clINIcAl EPIdEMIology IN MolEcUlAR oNcologyStefan Michiels

RAdIAtIoN EPIdEMIology, clINIcAl EPIdEMIology oF cANcER ANd SURvIvAlFlorent de Vathaire

lIfEStylE, gENES aNd hEalth: INtEgRatIvE tRaNS-gENERatIoNal EPIdEMIologyteam leader: Marie-christine boutron-Ruault

kEywoRdSFamily cohort, generations, lifestyle, genetics, epigenetics, health, cancer, chronic diseases, prevention, environment

Association between five lifestyle habits and cancer risk: Results from the E3N cohort.Dartois L, Fagherazzi G, Boutron-Ruault MC, Mesrine S, Clavel-Chapelon F. Cancer Prev Res (Phila). 2014 May;7(5):516-25.

Association between melanocytic nevi and risk of breast diseases: The French E3N prospective cohort. Kvaskoff M, Bijon A, Mesrine S, Vilier A, Baglietto L, Fournier A, Clavel-Chapelon F, Dossus L, Boutron-Ruault MC. PLoS Med. 2014 Jun 10;11(6):e1001660.

Erythrocyte membrane phospholipid fatty acid concentrations and risk of colorectal adenomas : a case-control nested in the French E3N-EPIC cohort study. Cottet V, Collin M, Gross AS, Boutron-Ruault MC, Morois S, Clavel-Chapelon F, Chajès V. Cancer Epidemiol Biomarkers Prev. 2013 Aug;22(8):1417-27.

Consumption of artificially and sugar-sweetened beverages and incident type 2 diabetes in the Etude Epidemiologique aupres des femmes de la Mutuelle Generale de l’Education Nationale-European Prospective Investigation into Cancer and Nutrition cohort.Fagherazzi G, Vilier A, Saes Sartorelli D, Lajous M, Balkau B, Clavel-Chapelon F. Am J Clin Nutr. 2013 Mar;97(3):517-23.

Estrogen-Progestagen Menopausal Hormone Therapy and Breast Cancer: Does Delay From Menopause Onset to Treatment Initiation Influence Risks? Fournier A, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F. J Clin Oncol. 2009 Nov 1;27(31):5138-43.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, team 9, cESP U1018, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 53 86e-mail: contact@e3n.fr ; contact@e4n.fr www.e3n.fr ; www.e4n.fr

tEaM MEMbERS:- Research: 17- Administration: 4- Databases: 5- Datamanagement: 7- Statistics: 4

SUMMaRy of thE RESEaRch toPIcS:The team’s research is mostly based on the E3N and E4N cohorts. It investigates the relationships between lifestyle and the major chronic diseases, with special interest for the study of the modern way of life in individuals of the same family, who thus share a genetic background and common environmental factors.

lines of research- To analyse the role of environmental and genetic factors, in the occurrence of and survival after cancer and other major chronic diseases (diabetes, cardiovascular diseases, neurological diseases...)

- To more specifically investigate the associations with lifestyle, metabolic factors (diet, physical activity), the use of hormonal treatments, reproductive factors, early life exposure, etc- To assess the relationship between chronic diseases and several biological markers (diet, hormonal milieu, genetic polymorphisms ...)- To analyse interactions between genetic characteristics and potential risk factors

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MEthodology aNd clINIcal EPIdEMIology IN MolEcUlaR oNcologyteam leader: Stefan Michiels

kEywoRdSBiostatistics – clinical trials- methodology – clinical epidemiology – oncology – biomarkers

Dose finding with longitudinal data: simpler models, richer outcomes. Paoletti X, Doussau A, Ezzalfani M, Rizzo E, Thiébaut R. Stat Med. 2015 Jun 24

Cost effectiveness of molecular profiling for adjuvant decision making in patients with node-negative breast cancer. Bonastre J, Marguet S, Lueza B, Michiels S, Delaloge S, Saghatchian M. J Clin Oncol. 2014;32(31):3513-9.

Preoperative chemotherapy for non-small-cell lung cancer : a systematic review and meta-analysis of individual participant data. NSCLC Meta-analysis Collaborative Group. Lancet. 2014;383(9928):1561-71

Clinical validity of circulating tumour cells in patients with metastatic breast cancer: a pooled analysis of individual patient dataBidard FC, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, Caldas C, Gazzaniga P, Manso L, Zamarchi R, de Lascoiti AF, De Mattos-Arruda L, Ignatiadis M, Lebofsky R, van Laere SJ, Meier-Stiegen F, Sandri MT, Vidal-Martinez J, Politaki E, Consoli F, Bottini A, Diaz-Rubio E, Krell J, Dawson SJ, Raimondi C, Rutten A, Janni W, Munzone E, Carañana V, Agelaki S, Almici C, Dirix L, Solomayer EF, Zorzino L, Johannes H, Reis-Filho JS, Pantel K, Pierga JY, Michiels S. Lancet Oncol. 2014;15(4):406-14

Dose-Finding Designs using a novel Quasi-Continuous Endpoint for Multiple Toxicities. Ezzalfani M, Zohar S, Qin R, Mandrekar, Le Deley MC. Stat Med. 2013;32(16):2728-46.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, team 2, cESP U1018,Service de biostatistique et d’Epidémiologie, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 41 44e-mail: Stefan.MIchIElS@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 10, Gustave Roussy- Faculty members: 3, Univ. Paris-Sud- Non-permanent researchers: 5- PhD students: 5

SUMMaRy of thE RESEaRch toPIcS:The recent revolution in –omics technology and the advent of targeted therapies have increased the interest in molecular biomarkers capable of predicting the diagnostic, the clinical outcome of cancer patients or the response to specific therapies (diagnostic, prognostic and predictive). There are many challenges in the appropriate processing of modern sequencing data and the integration of molecular data in clinical epidemiology. The development of personalised medicine implies the segmentation of common cancers in small groups of tumours with specific abnormalities. A new generation of clinical trial designs requiring repeated biomarker measurements and surrogate clinical endpoints is needed to evaluate treatment effects in trials with limited sample sizes. Large-scale collaborative individual patient

data meta-analyses are useful tools to provide high level of evidence on the efficacy and toxicity of anti-cancer therapies in molecularly defined strata. With the increasing number of therapies available for a specific indication in oncology, methods for network meta-analyses will be developed to compare their effectiveness. Because of the high costs associated with the new tandem diagnostic and therapeutic medicine, economic analyses will be needed to evaluate the strategy associating the biomarkers with the molecularly targeted treatments, which represents a new field of research. Once a potential biomarker has been identified for the prediction of diagnosis or clinical outcome of patients, evidence-based evaluation implies careful replication in other cohorts.

RadIatIoN EPIdEMIology, clINIcal EPIdEMIology of caNcER aNd SURvIval team leader: Florent de vathaire

kEywoRdSEpidemiology; biostatistics; radiation dose; cancer; iatrogenic effect; genetic; cohort

Ovarian reserve after treatment with alkylating agents during childhood. Thomas-Teinturier C, Allodji RS, Svetlova E, Frey MA, Oberlin O, Millischer AE, Epelboin S, Decanter C, Pacquement H, Tabone MD, Sudour-Bonnange H, Baruchel A, Lahlou N, De Vathaire F. Hum Reprod. 2015 Jun;30(6):1437-46.

Common variants at 9q22.33, 14q13.3, and ATM loci, and risk of differentiated thyroid cancer in the French Polynesian population. Maillard S, Damiola F, Clero E, Pertesi M, Robinot N, Rachédi F, Boissin JL, Sebbag J, Shan L, Bost-Bezeaud F, Petitdidier P, Doyon F, Xhaard C, Rubino C, Blanché H, Drozdovitch V, Lesueur F, de Vathaire F. PLoS One. 2015 Apr 7;10(4):e0123700.

Repair of ionizing radiation-induced DNA damage and risk of second cancer in childhood cancer survivors.Haddy N, Tartier L, Koscielny S, Adjadj E, Rubino C, Brugières L, Pacquement H, Diallo I, de Vathaire F, Averbeck D, Hall J, Benhamou S. Carcinogenesis. 2014;35:1745-9.

Functional data analysis in NTCP modeling: a new method to explore the radiation dose-volume effects. Benadjaoud MA, Blanchard P, Schwartz B, Champoudry J, Bouaita R, Lefkopoulos D, Deutsch E, Diallo I, Cardot H, de Vathaire F. Int J Radiat Oncol Biol Phys. 2014;90:654-63.

Radiation dose to the pancreas and risk of diabetes mellitus in childhood cancer survivors: a retrospective cohort study. de Vathaire F, El-Fayech C, Ben Ayed FF, Haddy N, Guibout C, Winter D, Thomas-Teinturier C, Veres C, Jackson A, Pacquement H, Schlumberger M, Hawkins M, Diallo I, Oberlin O. Lancet Oncol. 2012;13:1002-10.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, team 3, cESP U1018, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 41 40e-mail: florent.devathaire@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers : 3 - Technical staff : 11- Non-permanent researchers : 6- PhD students : 4- Others : 2

SUMMaRy of thE RESEaRch toPIcS:The team works on cancer epidemiology, with a focus on the effects of ionising radiation and iatrogenic effects of long-term cancer treatments. The implantation of the team in Gustave Roussy allows a close collaboration with the departments of radiotherapy, medical physics, nuclear medicine and paediatrics, and a unique position to carry out translational research. Since many years, the team has been following cohorts of subjects exposed to different dose levels of ionising radiation, including cohorts of cancer survivors. Over the last years, the study of the long-term outcome of patients treated for cancer, especially in childhood, has been one of the main fields of research of the team. This work requires estimating accurately the doses received in and outside of the fields during radiation therapy,

which is possible thanks to the software specifically developed by the team, and working on statistical methodological issues to better evaluate iatrogenic effects of long-term cancer treatments. Within the next years, the team will go further into its current research topics and develop new ones. Descriptive epidemiology of tobacco, alcohol, and cancer screening is now a part of the research field of the team. With the arrival of sociologists in the team, the social consequences of late effects of cancer treatments will also be addressed. The team is also developing projects on genetics, in cancer aetiology and in the study of long-term effects. In this framework, strengthening the collaboration with biologists, radiation therapists and clinicians, especially paediatricians, remains a key point in going further, and into developing innovative translational research projects.

• 2 patents • 1 ongoing industrial partnership

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UMR 9196 cNRS: MolEcUlaR PhySIology aNd Pathology of INfEctIoUS aNd ENdogENoUS REtRovIRUSESResearch Unit director: thierry heidmann

Single team Unit

kEywoRdS retrovirus, endogenous retrovirus, envelope protein, cell-cell fusion, immunosuppression, placentation, tumorigenesis, therapeutic molecules, vaccines

Retroviral envelope gene captures and syncytin exaptation for a placental function in marsupials.Cornelis G, Vernochet C, Carradec Q, Souquere S, Mulot B, Catzeflis F, Nilsson M, Pierron G, Heidmann O, Zeller U, Dupressoir A, Heidmann T. Proc. Natl. Acad. Sci. USA, 2015, 112, E487-496.

A targeted mutation within the FeLV envelope protein immunosuppressive domain to improve a canarypox-based FeLV vaccine. Schlecht-Louf G, Mangeney M, El-Garch H, Lacombe V, Poulet H, and Heidmann T. J Virol. 2014, 88, 992-1001.

The HERV-K human endogenous retrovirus envelope protein antagonises Tetherin antiviral activity.Lemaître C, Harper F, Pierron G, Heidmann T, Dewannieux M. J Virol. 2014, 88, 13626-37.

Retroviral envelope syncytin capture in an ancestrally diverged mammalian clade for placentation in the primitive Afrotherian tenrecs. Cornelis G, Vernochet C, Malicorne S, Souquere S, Tzika AC, Goodman SM, Catzeflis F, Robinson TJ, Milinkovitch MC, Pierron G, Heidmann O, Dupressoir A, Heidmann T. Proc Natl Acad Sci U S A, 2014, 111, E4332-41

Retrovirus infection in vivo requires an immune escape virulence factor encrypted in the envelope protein of oncoretroviruses. Schlecht-Louf, G., Renard, M., Mangeney, M., Letzelter, C., Richaud, A., Ducos, B., Bouallaga, I., and Heidmann, T. Proc. Natl. Acad. Sci. USA, 2010, 107, 3782-87.

ToP 5 PUBLICATIoNS

• Summary of the reSearch topicS :1) Molecular retrovirology : characterisation of endogenous retroviruses, identification of functional copies and of the cellular receptors ; physiopathology of the human endogenous retrovirus type K (HERV-K) ; role in tumorigenesis

2) Endogenous retroviral envelope genes : identification and characterisation of « syncytins », captured genes involved in placentation : demonstration of their role in syncytiotrophoblast formation via knockout mice, identification of independently captured genes among the major clades of placental mammals ; role in myoblast fusion and muscle fiber formation

3) Characterisation of the immunosuppressive (IS) domain of retroviral envelope proteins (ERVs, oncoretroviruses, lentiviruses) ; demonstration of their critical role for viral penetrance ; characterisation of the molecular and cellular targets of the IS domain and search for inhibitors to develop new therapeutic molecules

4) Developement of « improved » vaccine antigens deprived of immunosuppressive activity: application to a anti-FeLV veterinary vaccine (marketed mid-2012) ; development of HIV and HTLV optimised antigens, and of vectorised vaccines for pre-clinical and clinical assays

dEtaIlS: gustave Roussy, cNRS UMR 9196, 114, rue Edouard vaillant, 94805 villejuiftel. office: +33(0)1 42 11 54 33 e-mail: thierry.hEIdMANN@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 3 CNRS, 2 Inserm- Technical staff: 6 CNRS- Non-permanent researchers: 5 post doc- PhD students: 3

• 4 patents (2 with license)• 2 ongoing industrial partnerships• 1 start-up

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UMR 8200 cNRS: gENEtIc StabIlIty aNd oNcogENESISResearch Unit director: Patricia kannouche

cEll dIvISIoN ANd gENoMIc StAbIlItyOlivier Gavet

tlS PolyMERASES ANd gENoME PlAStIcItyPatricia Kannouche, Said Aoufouchi

REcoMbINAtIoN, REPAIR, RoS ANd cANcERBernard Lopez, Corinne Dupuy

REPAIR oF doUblE StRANd bREAkS ANd gENoME INtEgRIty (AtIP-AvENIR)Gerard Mazon

REPlIcAtIoN StRESS, gENoMIc INStAbIlIty ANd MItoSIS (ERc StARtINg gRANtS)Valeria Naim

dNA REPAIR SyNdRoMES Filippo Rosselli

dNA REPAIRMurat Saparbaev

cEll dIvISIoN aNd gENoMIc StabIlItyteam leader: olivier gavet

kEywoRdSKinase, Phosphatase, Cell division, Cancer, Signalling pathways, Biosensors

Deciphering the spatio-temporal regulation of entry and progression through mitosis.Gheghiani L, Gavet O.Biotechnol J. 2014 Feb;9(2):213-23.

Progressive activation of CyclinB1-Cdk1 coordinates entry to mitosis.Gavet O, Pines J.Dev Cell. 2010 Apr 20;18(4):533-43.

Activation of cyclin B1-Cdk1 synchronizes events in the nucleus and the cytoplasm at mitosis.Gavet O, Pines J.J Cell Biol. 2010 Apr 19;189(2):247-59.

Dynamic changes in Rap1 activity are required for cell retraction and spreading during mitosis.Dao VT, Dupuy AG, Gavet O, Caron E, de Gunzburg J.J Cell Sci. 2009 Aug 15;122(Pt 16):2996-3004.

Centrin4p, a novel mammalian centrin specifically expressed in ciliated cells.Gavet O, Alvarez C, Gaspar P, Bornens M.Mol Biol Cell. 2003 May;14(5):1818-34. Epub 2003 Feb 6.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, cNRS UMR 8200, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 62 25e-mail: olivier.gAvEt@gustaveroussy.fr

tEaM MEMbERS:- Faculty members: 1 - Université Pierre et Marie Curie, Paris (UPMC)- Technical staff: To be recruited- PhD students: 1 (UPMC)

SUMMaRy of thE RESEaRch toPIcS:A common hallmark of cancer cells is the appearance of genetic abnormalities whose progressive accumulation correlates with disease «aggressiveness». The main focus of our lab is to determine how is timely and reproducibly controlled mitotic commitment during any cell cycle to preserve genomic integrity.

Entry into mitosis is tightly controlled by a complex signalling network (Mitotic Entry Network or MEN), which ultimates in the activation of Cyclin B1-Cdk1, the master mitotic driver. DNA damages responses (DDR) modulate this network at different levels to control entry into mitosis.

Conversely, MEN inactivates DNA damage signalling around mitotic entry. Thus, entry into mitosis is finely tuned by an equilibrium between opposite signaling pathways. How this dynamic equilibrium is modulated in space and time during G2/M progression remains poorly characterized and is the main focus of our work.

To decipher the spatio-temporal regulation of key components of MEN versus DDR pathways we are currently combining genetically encoded FRET (Förster Resonance Energy Transfer) biosensors and real time live cell imaging assays.

• 1 patent

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tlS PolyMERaSES aNd gENoME PlaStIcIty- tlS Polymerases and cancer - group leader: Patricia kannouche- genome Plasticity and b cells - group leader: Said Aoufouchi

kEywoRdSTLS polymerase, DNA replication, heterochromatin, xeroderma pigmentosum, lymphomas, immunoglobulin gene diversification, AID

Aberrant C-terminal domain of polymerase η targets the functional enzyme to the proteosomal degradation pathway.Ahmed-Seghir S, Pouvelle C, Despras E, Cordonnier A, Sarasin A, Kannouche PL.DNA Repair (Amst). 2015 May;29:154-65.

The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability.Guervilly JH, Takedachi A, Naim V, Scaglione S, Chawhan C, Lovera Y, Despras E, Kuraoka I, Kannouche P, Rosselli F, Gaillard PH.Mol Cell. 2015 Jan 8;57(1):123-37.

Proteomic analysis reveals a FANCA-modulated neddylation pathway involved in CXCR5 membrane targeting and cell mobility.Renaudin X, Guervilly JH, Aoufouchi S, Rosselli F.J Cell Sci. 2014 Aug 15;127(Pt 16):3546-54.

Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells.Nguyen TV, Riou L, Aoufouchi S, Rosselli F.J Exp Med. 2014 Jun 2;211(6):1011-8.

Correlation of phenotype/genotype in a cohort of 23 xeroderma pigmentosum-variant patients reveals 12 new disease-causing POLH mutations.Opletalova K, Bourillon A, Yang W, Pouvelle C, Armier J, Despras E, Ludovic M, Mateus C, Robert C, Kannouche P, Soufir N, Sarasin A.Hum Mutat. 2014 Jan;35(1):117-28.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, cNRS UMR 8200, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 40 30e-mail: Patricia.kANNoUchE@gustaveroussy.fr ; e-mail: Said.AoUFoUchI@gustaveroussy.fr

tEaM MEMbERS:

SUMMaRy of thE RESEaRch toPIcS:translesion synthesis Process: a trade-off between limited mutagenesis and chromosomal instability (group1)Bulky lesions in the DNA can cause arrest of replicative polymerases. Failure to relieve such DNA replication stress can have dire consequences for the cell, as stalled replication forks are prone to collapse and could potentially lead to double-strand breaks (DSBs) that result to gross chromosomal instability that have a close link to tumorigenesis. Cells have evolved DNA damage tolerance strategies enabling the replication machinery to bypass fork-blocking lesions. One DDT pathway, the translesion synthesis (TLS) entails specialized low-fidelity polymerases, which can replicate damaged DNA, albeit in an error-prone manner. Therefore TLS has a conflicting role in genome stability maintenance, as it accounts for a large proportion of DNA damage-induced mutagenesis but prevents even more severe forms of genome instability such as chromosome rearrangements.

boosting the mutagenesis: Somatic hypermutation during Immunoglobulin diversification (group2)

In addition to their roles in the replication of damaged DNA, TLS polymerases have been co-opted into a number of other related processes. During development of the immune response, the antibody genes of vertebrates exhibit a particularly high rate of focused mutagenesis, known as somatic hypermutation, which is driven by activation-induced deaminase (AID). Although AID can only deaminate dC to dU, its action gives rise to mutations at all four bases in a series of reactions that crucially depend on the Y-family polymerases. The dU formed by the action of AID is removed by uracil DNA glycosylase (UNG), resulting in an abasic site. Direct replication of this abasic site involves REV1 and generates mutations at dG-dC base pairs. Recognition of dU can also result in the formation of a single-strand gap, and the filling of these gaps by polη results in mutations at dA–dT base pairs. One important question emerges from these different roles of TLS polymerases: How TLS polymerases are regulated and integrated with DNA replication, repair, epigenetic maintenance and chromatin architecture in mammalian cells? Detailed insight into these processes is highly topical for improving new concepts into cancer development and treatment.

REcoMbINatIoN, REPaIR, RoS aNd caNcER- Recombination, Repair and cancer - group leader: bernard lopez- RoS and radiocarcinogenesis - group leader: corinne dupuy

The cohesin complex prevents the end-joining of distant DNA double-strand ends. Camille Gelot, Josée Guirouilh-Barbat, Tangui Le Guen, Elodie Dardillac, Catherine Chailleux, Yvan Canitrot and Bernard S. Lopez (). Mol Cell, Volume 61, Issue 1, p15–26, 7 January 2016

NADPH oxidase DUOX1 promotes long-term persistence of oxidative stress after an exposure to irradiation.Ameziane-El-Hassani R, Talbot M, de Souza Dos Santos MC, Al Ghuzlan A, Hartl D, Bidart JM, De Deken X, Miot F, Diallo I, de Vathaire F, Schlumberger M, Dupuy C. Proc Natl Acad Sci U S A. 2015; 112(16):5051-6.

When an Intramolecular Disulfide Bridge Governs the Interaction of DUOX2 with Its Partner DUOXA2.Carré A, Louzada RA, Fortunato RS, Ameziane-El-Hassani R, Morand S, Ogryzko V, de Carvalho DP, Grasberger H, Leto TL, Dupuy C Antioxid Redox Signal. 2015 23(9):724-33

Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells.

Therese Wilhelm, Indiana Magdalou, Aurélia Barascu, Hervé Técher, Michelle Debatisse and Bernard S. Lopez Proc Natl. Acad. Sci. USA. 2014, 111.763-768.

A role for BLM in double strand break repair pathway choice: prevention of CtIP/Mre11-mediated alternative non-homologous end-joining.

Anastazja Grabarz, Josée Guirouilh-Barbat, Aurelia Barascu, Gaëlle Pennarun, Diane Genet, Emilie Rass, Susanne M. Germann, Pascale Bertrand, Ian D. Hickson and Bernard S. Lopez.Cell Reports, 2013, 5, 21-28.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, cNRS UMR 8200, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 63 25e-mail: bernard.loPEZ@gustaveroussy.fre-mail: corinne.dUPUy@gustaveroussy.fr

tEaM MEMbERS:

SUMMaRy of thE RESEaRch toPIcS:group 1: Recombination, Repair, and cancerDNA double strand breaks (DSB) are highly toxic lesions that can be produced by ionizing radiation, oxidative stress or DNA replication accidents. DSB can then generate genetic instability and thus can be at the origin of oncogenesis, senescence and developmental diseases.

Two main processes repair DSBs: Homologous recombination (HR) and Non-homologous End Joining (NHEJ).

Our research projects analyze the molecular and metabolic networks controlling DSB repair in mammals and the orientation of the repair toward one or the other pathway, and the consequences on genome stability, tumor initiation and progression.

group 2: RoS and radiocarcinogenesisDespite much progress in order to improve the benefit / risk ratio, the radiation causes many side effects. One consequence of side effects is an increased risk of initiation of new cancers such as thyroid cancer and the development of fibrosis. Basically, late effects of ionizing radiation involve reactive oxygen species (ROS). In cells, ROS are specifically produced by NADPH oxidases (NOX/DUOX). The thyroid expresses three of them. By producing ROS, the NADPH oxidases are suspected to be involved in genetic instability as well as in fibrogenesis process. With cellular and animal models and state-of-the-art technology, our objective is to dissect the molecular and mechanistic events from post-irradiation (IR)-induced ROS generation to genomic instability and radiocarcinogenesis as well as to fibrosis. During the last five years we developed transversal studies focused on thyroid oncogenesis and therapeutics, encompassing basic research (Corinne Dupuy), translational and clinical research (Martin Schlumberger, PU-PH, Director of the School of Cancer).

kEywoRdSDNA repair, Double strand break repair, Homologous recombination, Non-homologous end-joining, replication stress, oxidative stress, genome instability, tumor initiation, NADPH oxidases, Thyroid cancer and fibrosis

• 4 PATENTS

group 1: Recombination, Repair, RoS and cancer- Permanent researchers:

2 (CNRS)- Non-permanent researchers: 2- PhD students: 1

group 2: RoS and radiocarcinogenesis- Permanent researchers: 3 - Technical staff : 1 Assitant ingénieur

(AI, CDD CNRS)- Non-permanent researchers: 2 post doc- PhD students: 2

group1: tlS Polymerases and cancer- Permanent researchers : 1 CNRS, 1 CNRS (emeritus)- Technical staff : 1 CNRS- Non-permanent researchers : 1 post-doc - PhD students : 2 PhD students,

group2 : genome Plasticity and b cells- Permanent researchers :

1 Inserm - Faculty members : 1 Paris-Sud- Technical staff : 1 Paris-Sud

Paris-Sud

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REPaIR of doUblE StRaNd bREakS aNd gENoME INtEgRIty (atIP-avENIR)team leader: gerard Mazon

kEywoRdSHomologous Recombination, Double-strand break, Resolvases, Crossovers, Translocations, Chromosome Segregation defects

Ethylene oxide and propylene oxide derived N7-alkylguanine adducts are bypassed accurately in vivo.Philippin G, Cadet J, Gasparutto D, Mazon G, Fuchs RP.DNA Repair (Amst). 2014 Oct;22:133-6.

The Cdk/cDc14 module controls activation of the Yen1 holliday junction resolvase to promote genome stability.Eissler CL, Mazón G, Powers BL, Savinov SN, Symington LS, Hall MC.Mol Cell. 2014 Apr 10;54(1):80-93.

Mph1 and Mus81-Mms4 prevent aberrant processing of mitotic recombination intermediates.Mazón G, Symington LS.Mol Cell. 2013 Oct 10;52(1):63-74.

The Rad1-Rad10 nuclease promotes chromosome translocations between dispersed repeats.Mazón G, Lam AF, Ho CK, Kupiec M, Symington LS.Nat Struct Mol Biol. 2012 Sep;19(9):964-71.

Monitoring bypass of single replication-blocking lesions by damage avoidance in the Escherichia coli chromosome.Pagès V, Mazón G, Naiman K, Philippin G, Fuchs RP.Nucleic Acids Res. 2012 Oct;40(18):9036-43

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, cNRS UMR 8200, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 42 11 extension 38 76e-mail: gerard.MAZoN@gustaveroussy.fr

tEaM MEMbERS:- Technical staff: 1 Gustave Roussy (CDD)- Non-permanent researchers: 2 CNRS (CDD)

SUMMaRy of thE RESEaRch toPIcS:Double strand-break (DSB) repair is a critical pathway for genome integrity. Chromosome rearrangements (chromosome los, duplications, translocations...) and genomic aberrations occur in the absence of DSB repair or due to its incorrect repair. Homologous recombination (HR) is a multi-step pathway of critical importance for the DSB repair, but the way these multiple steps of HR are regulated is still unknown in detail, specially for the late recombination steps where there exist the risk of the formation of crossing over products that exchange genetic information between the chromosomes involved, with potential risk for loss heterozygosity and translocation formation.

The project of our team aims to better understand the regulation of the diferent players involved in the “crossing over” formation during DSB repair, using both yeast and human cell lines as models. The yeast model allows us to look at molecular intermediates at a level we still are unable to work in human cell lines. We draft phenotypes from mutations on regulation motifs on the different helicases and nucleases involved in crossover formation in the yeast model and then test them in the human homologs to see their relevance for the DSB repair process in a more relevant context for cancer research.

REPlIcatIoN StRESS, gENoMIc INStabIlIty aNd MItoSIS (ERc StaRtINg gRaNtS)team leader: valeria Naim

kEywoRdSgenomic instability, DNA replication stress, DNA damage, chromosomal instability, fragile sites, mitosis, Fanconi anaemia, chromosome segregation.

The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability.Guervilly JH, Takedachi A, Naim V, Scaglione S, Chawhan C, Lovera Y, Despras E, Kuraoka I, Kannouche P, Rosselli F, Gaillard PH.Mol Cell. 2015 Jan 8;57(1):123-37.

Autosomal-recessive SASH1 variants associated with a new genodermatosis with pigmentation defects, palmoplantar keratoderma and skin carcinoma.Courcet JB, Elalaoui SC, Duplomb L, Tajir M, Rivière JB, Thevenon J, Gigot N, Marle N, Aral B, Duffourd Y, Sarasin A, Naim V, Courcet-Degrolard E, Aubriot-Lorton MH, Martin L, Abrid JE, Thauvin C, Sefiani A, Vabres P, Faivre L.Eur J Hum Genet. 2015 Jul;23(7):957-62.

Defective endomitosis during megakaryopoiesis leads to thrombocytopenia in Fanca-/- mice.Pawlikowska P, Fouchet P, Vainchenker W, Rosselli F, Naim V.Blood. 2014 Dec 4;124(24):3613-23.

ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis.Naim V, Wilhelm T, Debatisse M, Rosselli F.Nat Cell Biol. 2013 Aug;15(8):1008-15

DNA synthesis by Pol η promotes fragile site stability by preventing under-replicated DNA in mitosis.Bergoglio V, Boyer AS, Walsh E, Naim V, Legube G, Lee MY, Rey L, Rosselli F, Cazaux C, Eckert KA, Hoffmann JS.J Cell Biol. 2013 Apr 29;201(3):395-408.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, cNRS UMR 8200, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 63 33e-mail: valeria.NAIM@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 1 Inserm- Technical staff: 1 CNRS- Non-permanent researchers: 1 CNRS- PhD students: 1

SUMMaRy of thE RESEaRch toPIcS:Our team is interested in the mechanisms of genome maintenance and the role of replication stress in genomic instability and cancer predisposition.

The model of study is Fanconi anaemia (FA), a genetic disorder characterised by chromosome instability, bone marrow failure and cancer predisposition.

Patients with FA display chromosomal instability, particularly at common fragile sites (CFS), genomic regions that are prone to breakage under replication stress conditions.

Alterations at CFS loci are commonly found in tumours and promote genomic instability from the early steps of cancer development.

Our research project aims at understanding the molecular causes and the functional consequences of CFS instability, using FA cellular and mouse models.

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dNa REPaIR SyNdRoMES team leader: Filippo Rosselli

kEywoRdSDNA repair, mitosis, Recombination, replication, Fanconi anaemia, cancer predisposition

The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability.Guervilly JH, Takedachi A, Naim V, Scaglione S, Chawhan C, Lovera Y, Despras E, Kuraoka I, Kannouche P, Rosselli F, Gaillard PH.Mol Cell. 2015 Jan 8;57(1):123-37.

Fanca deficiency reduces A/T transitions in somatic hypermutation and alters class switch recombination junctions in mouse B cells.Nguyen TV, Riou L, Aoufouchi S, Rosselli F.J Exp Med. 2014 Jun 2;211(6):1011-8.

Defective endomitosis during megakaryopoiesis leads to thrombocytopenia in Fanca-/- mice.Pawlikowska P, Fouchet P, Vainchenker W, Rosselli F, Naim V.Blood. 2014 Dec 4;124(24):3613-23.

ERCC1 and MUS81-EME1 promote sister chromatid separation by processing late replication intermediates at common fragile sites during mitosis.Naim V, Wilhelm T, Debatisse M, Rosselli F.Nat Cell Biol. 2013 Aug;15(8):1008-15.

The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities. V. Naim and F. Rosselli. Nature Cell Biology, 11, 761-768, 2009.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, cNRS UMR 8200, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 51 16e-mail: Filippo.RoSSEllI@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 1 CNRS, - Faculty members: 1 Paris-Sud- Technical staff: 1- Non-permanent researchers: 2 post-doc- PhD students: 2- Others: 1 PR Emérite Paris Sud

SUMMaRy of thE RESEaRch toPIcS:The ambition of the research’s projects that will be developed in the team over the coming years is: a) to achieve an improved understanding of the cellular and molecular mechanisms activated in response to genotoxic stress together with a better characterisation of the cellular fonctions of the FANC/BRCA pathway and its integration in the DNA damage response network; b) to precisely define its physiologic role(s) in healthy cells, tissues and individuals; c) to determine how its inactivation participate to cancer intiation and progression. Our goals span, indeed, from basic to translational research, fully integrating the scientific strategies and objectives of CNRS and Gustave Roussy Institute.

Our strategy will follow three axes to: Characterise at molecular and cellular level the DNA damage response (DDR) through the keyhole of the FANC/BRCA pathway.Identify the functions of the FANC pathway outside the DDR, to obtain a global understanding of the FA phenotype to better support patients care.Understand the role(s) of the FANC pathway in both differentiation and cancer, the physiological and pathological faces of the cell behaviour.

dNa REPaIRteam leader: Murat Saparbaev

kEywoRdSBase excision repair, Nucleotide incision repair, oxidative DNA damage, interstrand crosslinks, AP endonuclease, DNA glycosylase, active DNA demethylation, acquired resistant to anticancer therapy, crystal structure of DNA repair complex.

Characterization of DNA substrate specificities of apurinic/apyrimidinic endonucleases from Mycobacterium tuberculosis.Abeldenov S, Talhaoui I, Zharkov DO, Ishchenko AA, Ramanculov E, Saparbaev M, Khassenov B.DNA Repair (Amst). 2015 May 22;33:1-16.

Oxidatively Generated Guanine(C8)-Thymine(N3) Intrastrand Cross-links in Double-stranded DNA Are Repaired by Base Excision Repair Pathways.Talhaoui I, Shafirovich V, Liu Z, Saint-Pierre C, Akishev Z, Matkarimov BT, Gasparutto D, Geacintov NE, Saparbaev M.J Biol Chem. 2015 Jun 5;290(23):14610-7.

Conformational Dynamics of DNA Repair by Escherichia coli Endonuclease III.Kuznetsov NA, Kladova OA, Kuznetsova AA, Ishchenko AA, Saparbaev MK, Zharkov DO, Fedorova OS.J Biol Chem. 2015 Jun 5;290(23):14338-49.

Functional variants of human APE1 rescue the DNA repair defects of the yeast AP endonuclease/3’-diesterase-deficient strain.Wang Z, Ayoub E, Mazouzi A, Grin I, Ishchenko AA, Fan J, Yang X, Harihar T, Saparbaev M, Ramotar D.DNA Repair (Amst). 2014 Oct;22:53-66.

Pre-steady-state fluorescence analysis of damaged DNA transfer from human DNA glycosylases to AP endonuclease APE1.Kuznetsova AA, Kuznetsov NA, Ishchenko AA, Saparbaev MK, Fedorova OS.Biochim Biophys Acta. 2014 Oct;1840(10):3042-51.

ToP 5 PUBLICATIoNS

dEtaIlS: gustave Roussy, cNRS UMR 8200, 114, rue Edouard vaillant, 94805 villejuiftel.: +33(0)1 42 11 54 04e-mail: Murat.SAPARbAEv@gustaveroussy.fr

tEaM MEMbERS:- Permanent researchers: 2- Non-permanent researchers: 1- PhD students: 3

SUMMaRy of thE RESEaRch toPIcS:

The main research interest of the group is the field of DNA repair and mutagenesis, particularly in the various aspects of the enzymology of the repair of oxidative DNA damage and active DNA demethylation in mammalian cells. DNA is constantly subjected to chemical modifications endogenous and exogenous agents that induce frequently base and sugar lesions of different types, which are quickly repaired in vivo.

The clinical features of inherited human DNA repair deficient disorders such as Cockayne syndrome and Fanconi anaemia point to complex nature of endogenous oxidative

DNA damage which include bulky adducts, interstrand crosslinks (ICLs) and clustered lesions. Although, the repair pathways for simple non-bulky oxidative DNA damage are well established, the detailed molecular mechanisms of the removal of complex DNA lesions in mammalian cells remains poorly understood.

Our research aims to identify, at the molecular level, a relationship between a failure in DNA repair and genetic instability either at nucleotide (substitution, modification, insertion or deletion) or chromosome (genetic and epigenetic) level.