Mesothelioma – the 2nd expertise of FunGeST
Group Leader
PhD
Actual Projects
Pleural mesothelioma is a rare tumor mainly linked to asbestos exposure, characterized by a poor prognosis and an urgent need for precision medicine strategies. Therefore, predicting response to current treatments and developing new therapies that account for the molecular and cellular heterogeneity of pleural mesothelioma is crucial. To meet these challenges, we are focusing our research on 3 major axes:
(1) Deciphering intra-tumour heterogeneity: Single-cell omics and emerging spatial omics approaches will help define the tumour cell subpopulations present in a single biopsy. This will allow us to better understand their plasticity and phenotypic evolution, as well as to dissect the landscape of immune and stromal cells composing the tumour microenvironment.
(2) Developing therapeutic strategy: Functional screening using knockdown and knockout approaches, along with pharmacogenomics studies using our large patient-derived primary cell line biobank will lead to the identification of new therapeutic targets and new effective anti-tumour drugs that consider the phenotypic diversity of tumours.
(3) Identifying biomarkers of response to treatment: We will uncover signatures or biomarkers that predict response to treatment through multi-omics integrated analysis of tumor sample collection from patients enrolled in clinical trials or treated in real-life settings.
These projects are carried out in partnership with several clinical departments and associations. Close collaborations with other research laboratories allow us to explore areas such as the contribution of specific immune subpopulations to treatment resistance in preclinical models, and the identification of risk factors for pleural mesothelioma beyond asbestos exposure.
Past Works
Our research works has contributed to a better understanding of the molecular alterations but more importantly of the molecular heterogeneity of pleural mesothelioma. We were the first to propose a molecular classification of pleural mesothelioma that goes beyond the histologic classification and identifies specific molecular subtypes linked to mutational status. We also proposed a novel way to describe mesothelioma heterogeneity as a continuum using histo-molecular gradients that consider the main histologic types (epithelioid/sarcomatoid). We highlighted that these histo-molecular gradients identify tumours classified epithelioid at the histologic level, which are engaged towards the sarcomatoid phenotype. They do have strong prognostic value and may guide therapeutic strategies. Recent works have contributed to a better description of pleural mesothelioma anatomic intra-tumour heterogeneity. Importantly, we revealed genetic heterogeneity involving the major tumour suppressor gene NF2, as well as“hot” and “cold” immune profile of the tumour microenvironment depending on tumour positions in the thoracic cavity. Our results support the need to analyse multiple samples from distinct anatomical sites in order to estimate the prognosis or implement precision medicine strategies.
de Reynies et al, Clinical Cancer Research, 2014; Tranchant et al, Clinical Cancer Research, 2017; Blum et al, Nat Commun, 2019 ; Meiller Genome Med. 2021.
Fundings
Team
PhD
MD, PhD
MD, PhD
PharmD, PhD
-
Publications
Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma. Meiller C., Montagne F., Hirsch T.Z., Caruso S., de Wolf J., Bayard Q., Assié J.-B., Meunier L., Blum Y., Quetel L., Gibault L., Pintilie E., Badoual C., Humez S., Galateau-Sallé F., Copin M.-C., Letouzé E., Scherpereel A., Zucman-Rossi J., Le Pimpec-Barthes F., Jaurand M.-C. and Jean D. Genome Med. 2021 Jul 14. doi: 10.1186/s13073-021-00931-w.
Genetic alterations of malignant pleural mesothelioma: association to tumor heterogeneity and overall survival. Quetel L., Meiller C., Assié J. B., Blum Y., Imbeaud S., Montagne F., Tranchant R., de Wolf J., Caruso S., Copin M. C., Hofman V., Gibault L., Badoual C., Pintillie E., Hofman P., Monnet I., Scherpereel A., Le Pimpec-Barthes F., Zucman-Rossi J., Jaurand M. C., Jean D. Mol Oncol. 2020 Feb 21. doi: 10.1002/1878-0261.12651
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 Classification of Malignant Pleural Mesothelioma: Identification of a Poor Prognosis Subgroup Linked to the Epithelial-to-Mesenchymal Transition. de Reynies A., Jaurand M. C., Renier A., Couchy G., Hysi I., Elarouci N., Galateau-Salle F., Copin M. C., Hofman P., Cazes A., Andujar P., Imbeaud S., Petel F., Pairon J. C., Le Pimpec-Barthes F., Zucman-Rossi J., Jean D. Clin Cancer Res. 2014 Mar 02. doi: 10.1158/1078-0432.CCR-13-2429