Mesothelial carcinogenesis and molecular heterogeneity of human malignant pleural mesotheliomas
Responsable du Stage : Dr Didier Jean
Tél : 06.73.32.16.01 E-mail: didier.jean@inserm.fr
Université de Paris-Centre de Recherche des Cordeliers
Résumé du Projet de Stage
Malignant pleural mesothelioma (MPM) is a rare cancer that originates from the neoplastic transformation of mesothelial cells. This cancer is classified as an occupational and environment disease since asbestos is the major risk factor for the occurrence of this cancer. Up to now, MPM is still an incurable cancer and there is a strong need to develop new therapies. To find relevant strategies to MPM treatment, a better understanding of MPM biology is needed and tumor heterogeneity must be taken into account (Tranchant et al., 2018 – PMID: 29277245). A given cancer is a heterogeneous pathophysiological disease characterized by distinct molecular alterations and MPM is no exception to this finding.
Our recent research programs focused on the biological and molecular characterization of human MPM. We recently provided a comprehensive overview of the genetic landscape of MPM (Quetel et al., 2020 – PMID: 32083805). A transcriptomic study allows us to establish the first molecular classification of MPM defining subtypes characterized by different prognostic (de Reynies et al., 2014 – PMID: 24443521). Based also on genetic alterations, a new subtype was identified and a potential targeted therapy was proposed (Tranchant et al., 2016 – PMID: 28003305). More recently, we also characterized MPM heterogeneity by histo-molecular gradients with prognostic and therapeutic interests (Blum et al., 2019 – PMID: 30902996).
The M2 project will focus on the characterization of intra-tumor heterogeneity and the identification of genes and signal pathways discriminant according to the molecular phenotype of MPM. The main objective is to elaborate new therapeutic strategies taking account both inter- and intra-tumor heterogeneity. This project relies in our biological resource collections, consisting of MPM primary cell lines and of frozen tumors samples. This research involves several steps from the isolation and characterization of tumor cell subpopulations, identification of mutations in candidate genes, analysis of gene expression, and assessment of gene and pathway activities to the evaluation of specific inhibitors on mesothelial carcinogenesis. The M2 student will be supervised by a researcher and an engineer. He will benefit from our extensive biobanks of tumor samples, the strong interconnection with the clinical services taking care of MPM patients, and the expertise of the entire team in tumor genomics.
Publications de l’équipe relatives au projet de stage
Quetel L., Meiller C., Assie J. B., Blum Y., Imbeaud S., Montagne F., Tranchant R., de Wolf J., Caruso S., Copin M. C., Hofman V., Gibault L., Badoual C., Pintilie E., Hofman P., Monnet I., Scherpereel A., Le Pimpec-Barthes F., Zucman-Rossi J., Jaurand M. C., Jean D. Genetic alterations of malignant pleural mesothelioma: association to tumor heterogeneity and overall survival. Mol Oncol. 2020, 14: 1207-1223.
Blum Y., Meiller C., Quetel L., Elarouci N., Ayadi M., Tashtanbaeva D., Armenoult L., Montagne F., Tranchant R., Renier A., de Koning L., Copin M. C., Hofman P., Hofman V., Porte H., Le Pimpec-Barthes F., Zucman-Rossi J., Jaurand M. C., de Reynies A., Jean D. Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications. Nat Commun. 2019, 10: 1333.
Tranchant R., Quetel L., Tallet A., Meiller C., Renier A., de Koning L., de Reynies A., Le Pimpec-Barthes F., Zucman-Rossi J., Jaurand M. C., Jean D. Co-occurring mutations of tumor suppressor genes, LATS2 and NF2, in malignant pleural mesothelioma. Clin Cancer Res. 2017, 23: 3191-3202.
Ce projet s’inscrit-il dans la perspective d’une thèse :
oui X
ED d’appartenance : HOB « Hématologie – Oncogenèse – Biothérapies »
Equipe d’Accueil : « Génomique fonctionnelle des tumeurs solides » (FunGeST – Equipe 28)
Intitulé de l’Unité : Centre de Recherche des Cordeliers – Inserm UMRS.1138
Nom du Responsable de l’Unité : Jessica Zucman-Rossi
Nom du Responsable de l’Équipe :Jessica Zucman-Rossi
Adresse : Centre de Recherche des Cordeliers – 15 rue de l’école de médecine – 75006 Paris