Therapeutic Targets in Liver Tumors

FunGeST – From Genomics to Therapeutic Targets

Group Leader

Sandra REBOUISSOU
PhD - CR2
Inserm

Projects

“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 modeling 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.

Fundings

 

 

 

Team

Sandra REBOUISSOU
PhD - CR2
Inserm
Samantha SCHAEFFER
-
AI Inserm
Anna-Line CALATAYUD
PhD student
MESR Grant
Jill PILET
PhD student
FRM Grant
Massih Ningarhari
MD, PhD student
Fidjie BORDES
AI

Publications

APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547.

Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response. Caruso S, Calatayud AL, Pilet J, La Bella T, Rekik S, Imbeaud S, Letouzé E, Meunier L, Bayard Q, Rohr-Udilova N, Péneau C, Grasl-Kraupp B, de Koning L, Ouine B, Bioulac-Sage P, Couchy G, Calderaro J, Nault JC, Zucman-Rossi J, Rebouissou S. Gastroenterology. 2019 May 4. pii: S0016-5085(19)36771-X. doi: 10.1053/j.gastro.2019.05.001.

Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations. Adebayo Michael AO, Ko S, Tao J, Moghe A, Yang H, Xu M, Russell JO, Pradhan-Sundd T, Liu S, Singh S, Poddar M, Monga JS, Liu P, Oertel M, Ranganathan S, Singhi A, Rebouissou S, Zucman-Rossi J, Ribback S, Calvisi D, Qvartskhava N, Görg B, Häussinger D, Chen X, Monga SP. Cell Metab. 2019 May 7;29(5):1135-1150.e6. doi: 10.1016/j.cmet.2019.01.002. Epub 2019 Jan 31.

Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas. Nault JC, Couchy G, Caruso S, Meunier L, Caruana L, Letouzé E, Rebouissou S, Paradis V, Calderaro J, Zucman-Rossi J. Hepatology. 2018 Sep;68(3):964-976. doi: 10.1002/hep.29884. Epub 2018 Jun 6.

Note of caution: Contaminations of hepatocellular cell lines. Rebouissou S, Zucman-Rossi J, Moreau R, Qiu Z, Hui L. J Hepatol. 2017 Nov;67(5):896-897. doi: 10.1016/j.jhep.2017.08.002. Epub 2017 Aug 12.

More on Pubmed

Functional Genomics of Renal Cancer

Renal Cancer – 10 years of FunGeST expertise at the service of clinicians

Group Leaders

Benoit BEUSELINCK
MD
Oncologist in Leuven
Jessica ZUCMAN-ROSSI
MD, PhD
PUPHex Univeristy Paris 5

Actual Projects

 J Zucman-Rossi (PUPH), B Beuselinck (PUPH Louvain)

Fundings: Inca

We aim to translate the molecular classification of clear cell renal cancer into genome based clinical trial int cooperation with Sautès-Fridman team at CRC and clinicans at HEGP and Louvain. We also search for biomarkers predicting response to anti-angiogenic thearapies.

 

Past Works

Recently, we described a molecular classification of clear cell renal cancer (ccRCCs) into four robust subgroups with distinctive characteristics on multi-omics analyses. These subgroups are defined by various levels of myc activation, angiogenic activation and immune response associated with outcome of metastatic ccRCC treated with sunitinib. This classification has future application in patient care, in particular to predict drug response.

Beseulinck et al, Clin Cancer Research 2015.

Publications

Fibroblast Growth Factor Receptor-2 Polymorphism rs2981582 is Correlated With Progression-free Survival and Overall Survival in Patients With Metastatic Clear-cell Renal Cell Carcinoma Treated With Sunitinib. Vanmechelen M, Lambrechts D, Van Brussel T, Verbiest A, Couchy G, Schöffski P, Dumez H, Debruyne PR, Lerut E, Machiels JP, Richard V, Albersen M, Verschaeve V, Oudard S, Méjean A, Wolter P, Zucman-Rossi J, Beuselinck B. Clin Genitourin Cancer. 2019 Apr;17(2):e235-e246. doi: 10.1016/j.clgc.2018.11.002. Epub 2018 Nov 16.

Polymorphisms in the Von Hippel-Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors. Verbiest A, Lambrechts D, Van Brussel T, Couchy G, Wozniak A, Méjean A, Lerut E, Oudard S, Verkarre V, Job S, de Reynies A, Machiels JP, Patard JJ, Zucman-Rossi J, Beuselinck B. Clin Genitourin Cancer. 2018 Aug;16(4):266-273. doi: 10.1016/j.clgc.2018.01.013.

Molecular Subtypes of Clear-cell Renal Cell Carcinoma are Prognostic for Outcome After Complete Metastasectomy. Verbiest A, Couchy G, Job S, Caruana L, Lerut E, Oyen R, de Reyniès A, Tosco L, Joniau S, Van Poppel H, Van Raemdonck D, Van Den Eynde K, Wozniak A, Zucman-Rossi J, Beuselinck B. Eur Urol. 2018 Oct;74(4):474-480. doi: 10.1016/j.eururo.2018.01.042. Epub 2018 Feb 17.

Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma. Beuselinck B, Verbiest A, Couchy G, Job S, de Reynies A, Meiller C, Albersen M, Verkarre V, Lerut E, Méjean A, Patard JJ, Laguerre B, Rioux-Leclercq N, Schöffski P, Oudard S, Zucman-Rossi J. Acta Oncol. 2018 Apr;57(4):498-508. doi: 10.1080/0284186X.2017.1388927. Epub 2017 Nov 2.

Validation of VEGFR1 rs9582036 as predictive biomarker in metastatic clear-cell renal cell carcinoma patients treated with sunitinib. Beuselinck B, Jean-Baptiste J, Schöffski P, Couchy G, Meiller C, Rolland F, Allory Y, Joniau S, Verkarre V, Elaidi R, Lerut E, Roskams T, Patard JJ, Oudard S, Méjean A, Lambrechts D, Zucman-Rossi J. BJU Int. 2016 Dec;118(6):890-901. doi: 10.1111/bju.13585. Epub 2016 Aug 12.

RANK/OPG ratio of expression in primary clear-cell renal cell carcinoma is associated with bone metastasis and prognosis in patients treated with anti-VEGFR-TKIs. Beuselinck B, Jean-Baptiste J, Couchy G, Job S, De Reynies A, Wolter P, Théodore C, Gravis G, Rousseau B, Albiges L, Joniau S, Verkarre V, Lerut E, Patard JJ, Schöffski P, Méjean A, Elaidi R, Oudard S, Zucman-Rossi J. Br J Cancer. 2015 Nov 3;113(9):1313-22. doi: 10.1038/bjc.2015.352. Epub 2015 Oct 13.

Kidney cancer: Single nucleotide polymorphisms in mRCC-is their time up? Beuselinck B, Zucman-Rossi J. Nat Rev Urol. 2015 Aug;12(8):424-6. doi: 10.1038/nrurol.2015.149. Epub 2015 Jun 30. No

More publications 

 

 

 

Latest Publications

FunGeST latest publications

 

1: APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547. eCollection 2019. PMID: 31069152

 

2:Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response.

Caruso S, Calatayud AL, Pilet J, La Bella T, Rekik S, Imbeaud S, Letouzé E, Meunier L, Bayard Q, Rohr-Udilova N, Péneau C, Grasl-Kraupp B, de Koning L, Ouine B, Bioulac-Sage P, Couchy G, Calderaro J, Nault JC, Zucman-Rossi J, Rebouissou S. Gastroenterology. 2019 May 4. pii: S0016-5085(19)36771-X. doi: 10.1053/j.gastro.2019.05.001. [Epub ahead of print] PMID:31063779

 

3: Polyploidy spectrum: a new marker in HCC classification. Bou-Nader M, Caruso S, Donne R, Celton-Morizur S, Calderaro J, Gentric G, Cadoux M, L’Hermitte A, Klein C, Guilbert T, Albuquerque M, Couchy G, Paradis V, Couty JP, Zucman-Rossi J, Desdouets C. Gut. 2019 Apr 12. pii: gutjnl-2018-318021. doi: 10.1136/gutjnl-2018-318021. [Epub ahead of print] PMID:30979717

 

4: Dynamics and predicted drug response of a gene network linking dedifferentiation with beta-catenin dysfunction in hepatocellular carcinoma. Gérard C, Di-Luoffo M, Gonay L, Caruso S, Couchy G, Loriot A, Castven D, Tao J, Konobrocka K, Cordi S, Monga SP, Hanert E, Marquardt JU, Zucman-Rossi J, Lemaigre FP. J Hepatol. 2019 Apr 3. pii: S0168-8278(19)30195-3. doi: 10.1016/j.jhep.2019.03.024. [Epub ahead of print] PMID:30953666

 

5: A 17-Beta-Hydroxysteroid Dehydrogenase 13 Variant Protects From Hepatocellular Carcinoma Development in Alcoholic Liver Disease. Yang J, Trépo E, Nahon P, Cao Q, Moreno C, Letouzé E, Imbeaud S, Bayard Q, Gustot T, Deviere J, Bioulac-Sage P, Calderaro J, Ganne-Carrié N, Laurent A, Blanc JF, Guyot E, Sutton A, Ziol M, Zucman-Rossi J, Nault JC. Hepatology. 2019 Mar 25. doi: 10.1002/hep.30623. [Epub ahead of print] PMID:30908678

 

6: Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Blum Y, Meiller C, Quetel L, Elarouci N, Ayadi M, Tashtanbaeva D, Armenoult L, Montagne F, Tranchant R, Renier A, de Koning L, Copin MC, Hofman P, Hofman V, Porte H, Le Pimpec-Barthes F, Zucman-Rossi J, Jaurand MC, de Reyniès A, Jean D. Nat Commun. 2019 Mar 22;10(1):1333. doi: 10.1038/s41467-019-09307-6. PMID:30902996

 

7: Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations. Adebayo Michael AO, Ko S, Tao J, Moghe A, Yang H, Xu M, Russell JO, Pradhan-Sundd T, Liu S, Singh S, Poddar M, Monga JS, Liu P, Oertel M, Ranganathan S, Singhi A, Rebouissou S, Zucman-Rossi J, Ribback S, Calvisi D, Qvartskhava N, Görg B, Häussinger D, Chen X, Monga SP. Cell Metab. 2019 May 7;29(5):1135-1150.e6. doi: 10.1016/j.cmet.2019.01.002. Epub 2019 Jan 31. PMID:30713111

 

8: Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Bayard Q, Meunier L, Peneau C, Renault V, Shinde J, Nault JC, Mami I, Couchy G, Amaddeo G, Tubacher E, Bacq D, 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. Nat Commun. 2018 Dec 7;9(1):5235. doi: 10.1038/s41467-018-07552-9. PMID:30531861

 

9: Fibroblast Growth Factor Receptor-2 Polymorphism rs2981582 is Correlated With Progression-free Survival and Overall Survival in Patients With Metastatic Clear-cell Renal Cell Carcinoma Treated With Sunitinib. Vanmechelen M, Lambrechts D, Van Brussel T, Verbiest A, Couchy G, Schöffski P, Dumez H, Debruyne PR, Lerut E, Machiels JP, Richard V, Albersen M, Verschaeve V, Oudard S, Méjean A, Wolter P, Zucman-Rossi J, Beuselinck B. Clin Genitourin Cancer. 2019 Apr;17(2):e235-e246. doi: 10.1016/j.clgc.2018.11.002. Epub 2018 Nov 16. PMID:30527746

 

10: Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma. Tranchant R, Quetel L, Montagne F, De Wolf J, Meiller C, De Koning L, Le Pimpec-Barthes F, Zucman-Rossi J, Jaurand MC, Jean D. Lung Cancer. 2018 Dec;126:15-24. doi: 10.1016/j.lungcan.2018.10.015. Epub 2018 Oct 16. PMID:30527180

 

More on PubMed

Functional Genomics of Liver Tumors

FunGeST lab – an insight into liver tumors genomics

Group Leader

Jessica ZUCMAN-ROSSI
MD PhD
PUPHex University Paris 5

Actual Projects

Role of viral infection and integration in liver carcinogenesis

Collaborators: S Imbeaud (IR), C Peneau (PhD st), T La Bella (PhD st), J Zucman-Rossi (PUPH);

Involvement of pathogen agents in human carcinogenesis remain to be investigated. Our recent identification of AAV2 as the fourth virus involved in insertional mutagenesis prompt us to develop a project to evaluate consequences of HBV, HCV and AAV infections in liver tumorigenesis by integrating the analysis of viral and tumor genome alterations. Our aim is to reconstruct the natural history of the viruses (genome variation, replication, structural alterations, selection…) in the context of tumor cell selection in patients putatively treated by antiviral therapies or exposed to multiple pathogens. We will also search for additional pathogens in WGS data and collaborate with the international ICGC viruses project.

Fundings: LNCC, ANRS, Biomerieux Foundation

New molecular subtypes and cancer driver genes in pediatric liver tumors

Collaborators: G Morcrette (PhD st), E Letouzé (CR Inserm), J Pilet (PhD st), S Imbeaud (IR), G Couchy (IE, PhD st), Julien Calderaro (pathologist), JC Nault (MCUPH), J Zucman-Rossi (PUPH); in cooperation with SIOPEL,

Most of pediatric liver neoplasms are poorly analyszed at the genomic and molecular level. They include hepatocellular carcinomas (HCC), fibrolamellar carcinomas (FLC), hepatoblastomas (HB), transitional liver cell tumors (TLCT) and also benign neoplasms, hepatocellular adenomas (HCA) and focal nodular hyperplasias (FNH). We aim to perform an integrated genomic analysis of these pediatric hepatocellular tumors to better understand their mechanism of tumorigenesis. To this purpose, we have collected a series of 193 patients with pediatric frozen liver tumors part of the national HEPATOBIO tumor resource. Within this series, 48 cases/67 frozen tumor samples have been selected for whole genome sequencing (WGS) and RNA sequencing (RNAseq) within the GEPELIN project funded by France Génomique for the WGS part. Our specific aims are to (1) identify putative driver genes altered in pediatric tumors and validate them functionally (2) perform new transcriptomic classification to derive new altered pathways and diagnostic/prognostic markers, (3) characterize the mutational and chromosome rearrangement signatures to identify new mechanism of carcinogenesis (4) search for therapeutic targets. These results will be compared with the adult liver tumors data that we have accumulated in the lab.

Fundings:  LNCC, France Genomique.

Innovative genomic data integration to decipher the interaction between risk factors, endogeneous cellular processes and genomic alterations in liver carcinogenesis

Collaborators: E Letouzé , J Shinde , S Imbeaud (IR), L Meunier (PhD st), Q Bayard (M2), T Hirsch (Post-doc), J Zucman-Rossi (PUPH

In the last 5 years, we have generated large genomic data sets including 350 tumors analyzed by whole exome sequencing, 270 by RNA-seq, 250 by methylation arrays and 100 by whole genome sequencing. We will use this exceptional resource to unravel key questions in the natural history of liver cancers. (1) What mutational processes drive tumorigenesis? We have so far identified 10 point-mutation signatures associated with known (aflatoxin B1, tobacco) or unknown mutagenic processes in liver cancers. We will extend these analyses to signatures of indels and structural rearrangements, and perform a meta-analysis of all published liver cancer data sets to unravel the association of signatures with risk factors and predisposing variants. (2) What are the missing drivers in liver cancers? Analysis of coding mutations by us and others revealed tens of driver genes and pathways but 30% of tumors still have no identified driver event. In order to identify non-coding driver alterations, we will use whole genome and RNA-seq data to systematicallly screen for mutations and structural rearrangements modifying regulatory regions, chromatin context and 3’ UTR sequences and affecting mRNA expression and stability. (3) How to the genomic, epigenomic and transcriptional layers interact in tumor cells? We will develop innovative strategies to unravel the connexions between genomic alterations, DNA methylation and gene expression profiles. (4) What is the timing of genomic alterations along tumorigenesis? We and others have developed statistical approaches to time mutational signatures, copy-number alterations and driver events in the life history of a cancer using intra-tumor heterogeneity. We will conduct an ambitious project to analyze the evolution of genomic, transcriptional and micro-environment features in 25 patients with multiple samples along the treatment.

Fundings: Cancer environment, HTE HETCOLI, France Genomique, Canceropole

Genetic predisposition to benign and malignant liver tumors

E Letouzé (CR Inserm), P Nahon (PUPH), E Trepo (Post-doc), J Yang (Ph st), JC Nault (MCUPH), Zucman-Rossi (PUPH)

Candidate gene studies have uncovered a limited number of variants reproducibly linked to hepatocellular carcinoma (HCC). The HECAM project aims to identify newgermline variants predisposing to HCC in the French population and to test their ability to modify patient care in clinical practice. Therefore, a genome-wide association study will be performed in a multicenter cohort of chronic liver disease patients with (n = 2,066) and without (n = 2,666) HCC using the Illumina Infinium Global Screening Array including ~ 660,000 markers). Validation of the top variants will be performed in two French replication cohorts of cirrhotic patients included in HCC surveillance programs (n = 2,249). The performance for HCC risk stratification will be finally assessed through integration of genetic information into specific algorithm-based prediction models. An original integrative approach including somatic information already generated will be used for prioritizing variants impacting liver carcinogenesis. Finally, genotype-phenotype associations will be performed to build prognostic models. We also plan to analyze benign liver tumors to search for genetic predisposition to the development of hepatocellular adenoma in a cohort of 500 patients with in parallel an epidemiological study.

Fundings: HECAM, ANRS, AFEF

 

Team

Biologists

Jessica ZUCMAN-ROSSI
MD, PhD
PUPHex University Paris 5
Gabrielle COUCHY
PhD student (EPHE)
IE Inserm
Barkha GUPTA
MD PhD

Post Doc HECAM

Stefano CARUSO
PhD
Post Doc Labex
Théo HIRSCH
PhD
Post Doc Cancéropole
Tiziana LA BELLA
PhD student
University Paris 7
Camille PENEAU
PhD student
Inserm
Jie YANG
MD, PhD Student
Chinese grant
Benedicte NOBLET
-
IE Inserm
Guillaume MORCRETTE
MD, PhD Student
-
Alix DEMORY
MD, Master Student
Olivier MSIKA
MD, Master Student

Clinicians

Nathalie GANNE
MD
PUPH2 University Paris 13
Pierre NAHON
MD
PUPHex Univeristy Paris 5
Marianne ZIOL
MD
PUPH1 University Paris 13
Olivier SEROR
MD
PHUP2 University Paris 13
Jean- Charles NAULT
MD, PhD
MCU PH University Paris 13

Fundings

 

 

 

 

 

Latest Publications

APC germline hepatoblastomas demonstrate cisplatin-induced intratumor tertiary lymphoid structures. Morcrette G, Hirsch TZ, Badour E, Pilet J, Caruso S, Calderaro J, Martin Y, Imbeaud S, Letouzé E, Rebouissou S, Branchereau S, Taque S, Chardot C, Guettier C, Scoazec JY, Fabre M, Brugières L, Zucman-Rossi J. Oncoimmunology. 2019 Mar 28;8(6):e1583547. doi: 10.1080/2162402X.2019.1583547. eCollection 2019.

Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy. Dhanasekaran R, Nault JC, Roberts LR, Zucman-Rossi J. Gastroenterology. 2019 Jan;156(2):492-509. doi: 10.1053/j.gastro.2018.11.001. Epub 2018 Nov 4. Review.

Systemic AA Amyloidosis Caused by Inflammatory Hepatocellular Adenoma. 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. N Engl J Med. 2018 Sep 20;379(12):1178-1180. doi: 10.1056/NEJMc1805673.

Argininosuccinate synthase 1 and periportal gene expression in sonic hedgehog hepatocellular adenomas. Nault JC, Couchy G, Caruso S, Meunier L, Caruana L, Letouzé E, Rebouissou S, Paradis V, Calderaro J, Zucman-Rossi J. Hepatology. 2018 Sep;68(3):964-976. doi: 10.1002/hep.29884. Epub 2018 Jun 6

Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis. 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. Nat Commun. 2017 Nov 3;8(1):1315

Pro-angiogenic gene expression is associated with better outcome on sunitinib in metastatic clear-cell renal cell carcinoma. Beuselinck B, Verbiest A, Couchy G, Job S, de Reynies A, Meiller C, Albersen M, Verkarre V, Lerut E, Méjean A, Patard JJ, Laguerre B, Rioux-Leclercq N, Schöffski P, Oudard S, Zucman-Rossi J. Acta Oncol. 2018 Apr;57(4):498-508. doi: 10.1080/0284186X.2017.1388927. Epub 2017 Nov 2

More on Pubmed

Functional Genomics of Mesothelioma

Mesothelioma – the 2nd expertise of FunGeST

Group Leader

Didier JEAN
PhD-CR1
Inserm

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 (C2LN) 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, 201

Fundings

 

 

 

 

 

Team

Didier JEAN
PhD - CR1
Inserm
Email
Marie-Claude JAURAND
PhD
DR1 Inserm - Emeritat
Email
Clément MEILLER
-
IE Inserm
Email
Françoise LE PIMPEC BARTHES
MD
PUPH1 University Paris 5
Email
Arthur DUBOIS
M2 Student

 

Read More