Mesothelioma – the 2nd expertise of FunGeST
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.
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, 2017
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.
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.
[Molecular heterogeneity of malignant pleural mesotheliomas]. Tranchant R, Montagne F, Jaurand MC, Jean D. Bull Cancer. 2018 Jan;105(1):35-45. doi: 10.1016/j.bulcan.2017.11.007. Epub 2017 Dec 23. Review. French.
Co-occurring Mutations of Tumor Suppressor Genes, LATS2 and NF2, in Malignant Pleural Mesothelioma. Tranchant R, Quetel L, Tallet A, Meiller C, Renier A, de Koning L, de Reynies A, Le Pimpec-Barthes F, Zucman-Rossi J, Jaurand MC, Jean D. Clin Cancer Res. 2017 Jun 15;23(12):3191-3202. doi: 10.1158/1078-0432.CCR-16-1971. Epub 2016 Dec 21.