Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications

Yuna Blum, Clément Meiller, Lisa Quetel, Nabila Elarouci, Mira Ayadi, Danisa Tashtanbaeva, Lucile Armenoult, François Montagne, Robin Tranchant, Annie Renier, Leanne Koning, Marie-Christine Copin, Paul Hofman, Véronique Hofman, Henri Porte, Françoise Pimpec-Barthes, Jessica Zucman-Rossi, Marie-Claude Jaurand, Aurélien Reyniès () and Didier Jean ()
Additional contact information
Yuna Blum: Ligue Nationale Contre Le Cancer
Clément Meiller: Sorbonne Universités, Inserm, UMRS-1138
Lisa Quetel: Sorbonne Universités, Inserm, UMRS-1138
Nabila Elarouci: Ligue Nationale Contre Le Cancer
Mira Ayadi: Ligue Nationale Contre Le Cancer
Danisa Tashtanbaeva: Sorbonne Universités, Inserm, UMRS-1138
Lucile Armenoult: Ligue Nationale Contre Le Cancer
François Montagne: Sorbonne Universités, Inserm, UMRS-1138
Robin Tranchant: Sorbonne Universités, Inserm, UMRS-1138
Annie Renier: Sorbonne Universités, Inserm, UMRS-1138
Leanne Koning: PSL Research University
Marie-Christine Copin: Université de Lille
Paul Hofman: Laboratoire de Pathologie Clinique et Expérimentale (LPCE) et biobanque (BB-0033-00025), CHRU de Nice
Véronique Hofman: Laboratoire de Pathologie Clinique et Expérimentale (LPCE) et biobanque (BB-0033-00025), CHRU de Nice
Henri Porte: Hôpital Calmette - CHRU de Lille
Françoise Pimpec-Barthes: Sorbonne Universités, Inserm, UMRS-1138
Jessica Zucman-Rossi: Sorbonne Universités, Inserm, UMRS-1138
Marie-Claude Jaurand: Sorbonne Universités, Inserm, UMRS-1138
Aurélien Reyniès: Ligue Nationale Contre Le Cancer
Didier Jean: Sorbonne Universités, Inserm, UMRS-1138

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract Malignant pleural mesothelioma (MPM) is recognized as heterogeneous based both on histology and molecular profiling. Histology addresses inter-tumor and intra-tumor heterogeneity in MPM and describes three major types: epithelioid, sarcomatoid and biphasic, a combination of the former two types. Molecular profiling studies have not addressed intra-tumor heterogeneity in MPM to date. Here, we use a deconvolution approach and show that molecular gradients shed new light on the intra-tumor heterogeneity of MPM, leading to a reconsideration of MPM molecular classifications. We show that each tumor can be decomposed as a combination of epithelioid-like and sarcomatoid-like components whose proportions are highly associated with the prognosis. Moreover, we show that this more subtle way of characterizing MPM heterogeneity provides a better understanding of the underlying oncogenic pathways and the related epigenetic regulation and immune and stromal contexts. We discuss the implications of these findings for guiding therapeutic strategies, particularly immunotherapies and targeted therapies.

Date: 2019
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DOI: 10.1038/s41467-019-09307-6

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