Mesothelioma – the 2nd expertise of FunGeST

Group Leader

Actual Projects

D Jean, MC Jaurand, F Le Pimpec-Barthes, C Meiller, W Blum, L Quetel. Fundings: LNCC IdF and CIT, Chancellerie des Universités de Paris-Legs Poix

Malignant pleural mesothelioma (MPM) is a rare tumor, with a poor prognosis mainly due to the lack of efficient treatment. It is therefore important to develop new therapies that take into account the heterogeneity of MPM at the molecular level. We have recently defined a molecular classification of MPMs that defines two main groups C1 and C2. A subgroup of C2, with a double mutation in the Hippo, NF2 and LATS2 pathway genes, was identified. The C2 group and the NF2 / LATS2 double mutant subgroup contain MPMs from patients with a very poor prognosis. We  focus on four major aims:

(1) Refine the molecular classification of malignant pleural mesothelioma and transfer it to clinic: Integrated multi-omic analysis using our large collection of tumors will allow to identify new tumor subgroups. Identification of specific biomarkers and development of prediction tools should facilitate the implementation of this classification to clinic.

(2) Determine the mechanisms of mesothelial carcinogenesis: Functional analysis using our cell lines biobank will lead to define the contribution of specific gene alterations and signal pathways to carcinogenesis.

(3) Develop therapeutic strategy: High-content screening and validation using in vitro and in vivo models will be used to study the correlation between anti-tumor compounds sensibility and the molecular phenotype and will constitute a first step toward precision medicine for mesothelioma.

(4) Characterize intra-tumor heterogeneity: Molecular analysis will be performed to explore heterogeneity of tumor samples at different anatomical sites and presence of cancer stem cells.

 

Past Works

We performed a genetic and transcriptomic characterization of malignant pleural mesothelioma (MPM) using our tumor biobanks. We identified the first recurrent oncogenic mutation in the TERT promoter and showed this alteration was frequent in MPM of the sarcomatoid subtype (1). Based on transcriptomic data, we defined a robust molecular classification consisting of two groups (C1 and C2) with different molecular profiles, gene alterations, histology subtypes, and survival outcomes. One of the major interests was to separate the epithelioid MPM, the most frequent histologic subtype, according to their survival prognosis (2). Recently, by coupling transcriptomic and genetic analysis, we identified a new specific MPM molecular subgroup (C2^LN) characterized by a co-occurring mutation in LATS2 and NF2 tumor suppressor genes. We identified a specific biomarker and highlighted a high sensitivity to mTOR/PI3K/AKT (PF-04691502) inhibitor treatment for this subgroup (3).

Tallet et al, Oncogene, 2014; de Reynies et al… Jean, Clinical Cancer Research, 2014; Tranchant et al, Clinical Cancer Research, 2017 

Fundings

 

 

 

 

 

Team

Didier JEAN

CR1 Inserm

PhD

Marie-Claude JAURAND

DR1 Inserm - Emeritat

PhD

Françoise LE PIMPEC BARTHES

PUPH - UPHP

MD, PhD

Clément MEILLER

IE Inserm

Jean-Baptiste ASSIE

MCU-PH AP-HP

MD, PhD

Maya ARNOULD

PhD student

Khawla BENNANI ZIATNI

PhD student

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Guillaume TOSATO

Postdoctoral researcher

PharmD, PhD

Camille BOANO

M2 student

 

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FunGeST Lab – A Multidisciplinary, Young & Motivated Team

Brief history of the team

FunGeST “Functional genomics of solid tumors”, directed by Jessica Zucman-Rossi, was created in 2005, as Inserm U674, it was renewed in 2009 and 2014 as UMR1162, ranked “incontournable” by Inserm as a mixed structure endorsed by four entities: Inserm, Universities Paris Diderot, Paris Descartes and Paris Nord. It is currently located at the University Hematology Institute site in a building managed by the CEPH (Centre d’Etude du Polymorphisme Humain, Foundation Jean Dausset). Since January 2019, the lab take part of Centre de Recherche des Cordeliers  Research Center – Inserm UMR S1138 as team 28.

Jessica Zucman-Rossi, is professor of Medicine in Oncology (PUPHex) at university Paris Descartes and HEGP, full time for research. She directed the Inserm U674,  U1162 and UMRS1138 – team 28 since 2007, was chairman of the Inserm scientific committee devoted to Oncology, Genetics and Bioinformatics from 2012 to 2016. She is editor at Journal of Hepatology (IF=12.4), executive secretary of the International Liver Cancer Association (ILCA). She published 157 original papers and has an international recognition in the field of genomics of human cancers and more specifically in liver tumors. Since January 2019 Pr Zucman-Rossi-Rossi is the director of the Cordeliers Research Center.

Our missions

Our mission is to develop basic genomic approaches based on human tumors analyses to identify new mechanisms of tumorigenesis and to transfer this knowledge into biomarkers and therapeutic targets that could be introduced in clinical care. In particular, we aim to identify new genomic alterations and mechanisms of carcinogenesis. We also aim to identify new risk factors and genetic predispositions promoting the development of tumors. Our general strategy is based on the omic’s analyses of large cohorts of patients with liver tumors (benign and malignant), mesothelioma and clear cell renal carcinoma. The group was pioneer in the elucidation of the molecular classification of benign and malignant liver tumors. Then we perform (1) functional validation using cell and animal models and (2) we translate our findings into the clinics to improve surveillance, diagnosis, prognosis, treatment and follow-up of the patients.

Our task forces

The team include a total of 39 peoples  organized in 5 groups with their founded projects:

• “Functional Genomics of Liver tumors” led by Jessica Zucman-Rossi focusing on the characterization of genomic alterations in benign and malignant liver tumors, functional validation, identification of new risk factors and genetic predisposition and translation to the clinics.
• “Functional Genomics of Mesothelioma” led by Didier Jean  focusing on the pathogenesis of mesothelioma, search for new therapeutic targets with genomic approaches.
• “Therapeutic Targets in liver tumors” led by Sandra Rebouissou & Jean-Charles NAULT focusing on the identification of therapeutic targets in liver tumors.
• “HPV Tumors ” led by Hélène PERE & David VEYER focusing on the pathogenesis and the characterization of the Human Papillomavirus tumors.
• “Genomics of Pediatric Liver Tumors” led by Theo HIRSCH focusing on the development and application of innovative strategies for integrative genomic data analysis of pediatric liver tumors

 

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FunGeST Projects

We aim to develop scientific projects with specific objectives to integrate innovative tumor genomic characterizations with metabolism and immune response to identify new biomarkers and therapeutic targets useful for the patients. To this aim, we focus on 3 major types of cancer: liver, mesothelioma and renal carcinoma, in close collaboration with clinicians and pathologists. Thanks to our future moving at the Centre de Recherche des Cordeliers our team will benefit from close collaborations with other teams involved in Onco-Immunology, Metabolism and developing innovative genomic approaches.