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Functional Genomics of Solid Tumors - FunGeST

The team is directed by Jessica Zucman-Rossi M.D., Ph.D., professor of Medicine in Oncology (PUPHex) at university Paris Descartes and “Hopital Européen Georges Pompidou”.


We develop translational genomic approaches based on human tumors analyses to identify new mechanisms of tumorigenesis (e.g. new genomic alterations, clinical/genomic risk factors) and to propose biomarkers and therapeutic targets that could be introduced in clinical practice. Our general strategy is based on the large-scale genomic analysis of large cohorts of patients with liver tumors (benign and malignant), mesothelioma and renal cancer. The team is organized in 4 groups with their projects:

“Functional Genomics of Liver and Renal Tumors”, led by Jessica Zucman-Rossi M.D., Ph.D., is focused on the characterization and functional validation of genomic alterations in benign and malignant liver tumors, identification of new clinical/genomic risk factors, and ultimately, translation to the clinics. Particularly, this part of the lab studies the involvement of viral infections and their integration in liver carcinogenesis by integrating the analysis of viral and tumor genome alterations. Recently, the team focused on pediatric liver tumors to identify new molecular subtypes and cancer driver genes using an integrated genomic analysis (whole genome, RNA sequencing and DNA methylation profiling) taking advantage of a unique set of frozen pediatric liver tumors from 193 patients. We also identified a molecular classification of clear cell renal cancer that is used for prospective clinical trial to search for factors predicting response to tyrosine kinase inhibitors and to immunotherapy.


ll“Computational Cancer Genome Analysis”, led by Eric Letouzé Ph.D., develops innovative strategies for integrative genomic data analysis in order to decipher the interaction between clinical risk factors, endogenous cellular processes and genomic alterations in liver carcinogenesis. In the last years, the lab has generated various large next-generation sequencing data sets (whole genome, whole exome, RNA sequencing and DNA methylation profiles). This exceptional resource is used to answer key questions about the natural history of liver cancers. More specifically, Eric Letouzé’s collaborators analyze the evolution of genomic, transcriptional, and micro-environment features along tumor development and treatment. They also aim to identify new inherited genetic variants predisposing to liver tumors and develop clinico-molecular predictive models that could be tested in clinical practice.


“Therapeutic Targets in liver tumors”, led by Sandra Rebouissou Ph.D., develops an integrated approach that extends from the study of the molecular basis of tumor initiation and progression to applications of targeted treatment and the identification of biomarkers predicting the therapeutic response. For this purpose, they develop two main research axes: 1) translational studies based on screening of anti-tumor molecules on large collections of adult and pediatric human liver cancer cell lines characterized extensively at the molecular level, combined with genomic analysis of tumor samples from patients included in clinical trials in order to link tumor molecular alterations and microenvironment to the clinical therapeutic response.2) basic studies aimed at modelling in cellulo and in vivo the genetic alterations identified in human tumors in order to better identify the driver genes and their role in liver oncogenesis, and to understand the mechanisms of oncogenic cooperations.


“Functional Genomics of Mesothelioma”, led by Didier Jean Ph.D., studies pathogenesis of malignant pleural mesothelioma (MPM), a rare tumor, with poor prognosis due to the lack of efficient treatment. They focus on refining the molecular classification of MPM to better consider tumor heterogeneity between patients by integrating multi-omic analysis using their large collection of tumor samples. The objectives are to identify new tumor homogeneous subtypes associated with specific biomarkers and to transfer the MPM molecular classification to clinic. They also characterize intra-tumor heterogeneity focusing on heterogeneity of tumor samples at different anatomical sites and on the presence of different tumor cell entities in MPM. Didier Jean’s team also performs functional analysis using their cell lines biobank and develop therapeutic strategies by screening anti-tumor compounds.


For more informations, visit the team website: www.zucmanlab.com

 

Team Leader:  Jessica ZUCMAN-ROSSI (PU-PH; Univ Paris Descartes)

 

Team Members :
Researchers: Benoit BEUSELINK PU-PH; Univ Louvain), Fabien CALVO (PU-PH; Univ Paris Diderot), Nathalie GANNE-CARRIE (PU-PH; Univ Paris 13), Marie-Claude JAURAND (DR em; Inserm), Didier JEAN (CR; Inserm), Françoise LE PIMPEC BARTHES (PUPH; Univ Paris Descartes), Eric LETOUZE (CR; Inserm), Laura MOLINA (CR; INSERM), Guillaume MORCRETTE (AHU; CDD), Pierre NAHON (PUPH; Univ Paris 13), Jean-Charles NAULT (MCU-PH; Univ Paris 13),  Sandra REBOUISSOU (CR, Inserm), Olivier SEROR (PUPH; Univ Paris 13), Marianne ZIOL (PUPH; Univ Paris 13).

Technical Staff: Fidjie BORDES (AI, CDD), Gabrielle COUCHY (IE; Inserm), Sandrine IMBEAUD (IR; CNRS),  Clément MEILLER (IE; Inserm), Bénédicte NOBLET (IE, CDD), Samantha SCHAEFFER (AI; Inserm),

Young Researchers:  Gupta BARKHA (Post-Doc), Quentin BAYARD (PhD Student), Stefano CARUSO (Post-Doc), Anna-Line CATALAYUD (PhD Student), Théo HIRSCH (Post-Doc), Yannick LADEIRO (Post-Doc), Léa MEUNIER (PhD Student), Ana NEGULESCU (Post-Doc), Massih NINGARHARI (PhD Student), Camille PENEAU (PhD Student), Jill PILET (PhD Student), Eric TREPO (Post Doc),  Jie YANG (PhD Student). 

Students: Alix DEMORY (Master Student). Amélie ROEHRIG (Master Student).

Publications

  • Bayard Q, Meunier L, Peneau C, Renault V, Shinde J, Nault JC, Mami I, Couchy G, Amaddeo.G, Tubacher E, Bacq B, Meyer V, La Bella T, Debaillon-Vesque A, Bioulac-Sage P, Seror O, Blanc JF, Calderaro J, Deleuze JF, Imbeaud S, Zucman-Rossi J, Letouzé E. Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Nature Communications, 2019 in press.
  • Costentin CE, Layese R, Bourcier V, Cagnot C, Marcellin P, Guyader D, Pol S, Larrey D, De Lédinghen V, Ouzan D, Zoulim F, Roulot D, Tran A, Bronowicki JP, Zarski JP, Riachi G, Calès P, Péron JM, Alric L, Bourlière M, Mathurin P, Blanc JF, Abergel A, Serfaty L, Mallat A, Grangé JD, Attali P, Bacq Y, Wartelle C, Dao T, Thabut D, Pilette C, Silvain C, Christidis C, Nguyen-Khac E, Bernard-Chabert B, Zucman D, Di Martino V, Sutton A, Letouzé E, Imbeaud S, Zucman-Rossi J, Audureau E, Roudot-Thoraval F, Nahon P; ANRS CO12 CirVir Group. Compliance With Hepatocellular Carcinoma Surveillance Guidelines Associated With Increased Lead-Time Adjusted Survival of Patients With Compensated Viral Cirrhosis: A Multi-Center Cohort Study. Gastroenterology. 2018 Aug;155(2):431-442.e10
  • Calderaro J, Letouzé E, Bayard Q, Boulai A, Renault V, Deleuze JF, Bestard O, Franco D, Zafrani ES, Nault JC, Moutschen M, Zucman-Rossi J*. Systemic AA amyloidosis cased by inflammatory hepatocellular adenoma. The New England Journal of Medicine. 2018, 379(12):1178-1180.
  • Ziol M, Poté N, Amaddeo G, Laurent A, Nault JC, Oberti F, Costentin C, Michalak S, Bouattour M, Francoz C, Pageaux GP, Ramos J, Decaens T, Luciani A, Guiu B, Vilgrain V, Aubé C, Derman J, Charpy C, Zucman-Rossi J, Barget N, Seror O, Ganne-Carrié N, Paradis V, Calderaro J. Macrotrabecular-massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance. Hepatology 2018 Jul;68(1):103-112.
  • Letouzé E*, Shinde J*, Renault V, Couchy G, Blanc JF, Tubacher E, Bayard Q, Bacq D, Meyer V, Semhoun J, Bioulac-Sage P, Prévôt S, Azoulay D, Paradis V, Imbeaud S, Deleuze JF, Zucman-Rossi J. Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. Nature Communications 2017 Nov 3;8(1):1315. *equally contributed
  • Rebouissou S*, La Bella T*, Rekik S, Imbeaud S, Calatayud AL, Rohr-Udilova N, Martin Y, Couchy G, Bioulac-Sage P, Grasl-Kraupp B, de Koning L, Ganne N, Nault JC, Ziol M, Zucman-Rossi J*. Proliferation markers are associated with MET expression in hepatocellular carcinoma and predict tivantinib sensitivity in vitro. Clinical Cancer Research 2017 23(15):4364-4375. *equally contributed
  • Nault JC, Couchy G, Balabaud C, Morcrette G, Caruso S, Blanc JF, Bacq Y, Calderaro J, Paradis V, Ramos J, Scoazec JY, Gnemmi V, Sturm N, Guettier C, Fabre M, Savier E, Chiche L, Labrune P, Selves J, Wendum D, Pilati C, Laurent A, De Muret A, Le Bail B, Rebouissou S, Imbeaud S; GENTHEP investigators., Bioulac-Sage P, Letouzé E, Zucman-Rossi J. Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation. Gastroenterology. 2017, Mar;152(4):880-894.
  • Rebouissou S*, Franconi A*, Calderaro J, Letouzé E, Imbeaud S, Pilati C, Nault JC, Couchy G, Laurent A, Balabaud C, Bioulac-Sage P, Zucman-Rossi J**. Genotype-phenotype correlation of CTNNB1 mutations with different ß-catenin activation levels in liver tumors. Hepatology.2016, 24, 6, 2047-2061.*equally contributed
  • Nault JC, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G, Letouzé E, Pilati C, Verret B, Blanc JF, Balabaud C, Calderaro J, Laurent A, Letexier M, Bioulac-Sage P, Calvo F, Zucman-Rossi J Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nature Genetics. 2015, 47(10):1187-93,
  • Schulze K*, Imbeaud S*, Letouzé E*, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL, Pinyol R, Pelletier L, Balabaud C, Laurent A, Blanc J-F, Mazzaferro V, Calvo C, Villanueva A, Nault JC, Bioulac-Sage P, Stratton MR, Llovet JM, Zucman-Rossi J*. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nature Genetics. 2015, 47(5):505-11. *equally contributed
  • Amaddeo G*, Cao Q*, Ladeiro Y, Imbeaud S, Nault JC, Jaoui D, Gaston Mathe Y, Laurent C, Laurent A, Bioulac-Sage P, Calderaro J, Zucman-Rossi J*. Integration of tumor and viral genomic characterizations in HBV related hepatocellular carcinomas. Gut. 2015, 64(5):820-9.*Equally contributed
  • Benoit Beuselinck*, Sylvie Job*, Etienne Becht, Alexandra Karadimou, Virginie Verkarre, Gabrielle Couchy, Nicolas Giraldo, Nathalie Rioux-Leclercq, Vincent Molinié, Mathilde Sibony, Reza Elaidi, Corinne Teghom, Jean-Jacques Patard, Arnaud Méjean, Wolf Herman Fridman, Catherine Sautès-Fridman, Aurélien de Reyniès, Stéphane Oudard, Jessica Zucman-Rossi*. Molecular subtypes of clear cell renal cell carcinoma are associated to sunitinib response in the metastatic setting. Clinical Cancer Research. 2015, 21(6):1329-39. *equally contributed
  • Pilati C, Letouzé E, Nault JC, Imbeaud S, Boulai A, Calderaro J, Poussin K, Franconi A, Couchy G, Morcrette G, Mallet M, Taouji S, Balabaud C, Terris B, Canal F, Paradis V, Scoazec JY, de Muret A, Guettier C, Bioulac-Sage P, Chevet E, Calvo F, Zucman-Rossi J* Integrative genomic profiling of hepatocellular adenomas reveals recurrent FRK activating mutations and mutational processes of malignant transformation, Cancer Cell. 2014, 25(4):428-41.
  • Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J. High frequency of telomerase reverse transcriptase promoter somatic mutations in hepatocellular carcinoma and pre-neoplastic lesions. Nature Communications. 2013, 26;4:2218.
  • Nault JC, De Reyniès A, Villanueva A, Calderaro J, Rebouissou S, Couchy G, Decaens T, Franco D, Imbeaud S, Rousseau F, Azoulay D, Saric J, Blanc JF, Balabaud C, Bioulac-Sage P, Laurent A, Laurent-Puig P, Llovet JM, Zucman-Rossi J. A Hepatocellular Carcinoma 5-Gene Score Associated With Survival of Patients After Liver Resection. Gastroenterology. 2013, 145(1):176-87
  • Guichard C*, Amaddeo G*, Imbeaud S*, Ladeiro Y, Pelletier L, Ben Maad I, Calderaro J, Bioulac-Sage P, Letextier M, Degos F, Clément B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouzé E, Calvo F, Zucman-Rossi J*. Integrated analysis of somatic mutations and focal copy number changes identifies key genes and pathways in hepatocellular carcinoma. Nature Genetics. 2012, 44, 694–698, 2012. *equally contributed.

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