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Nat Commun. 2019 Mar 22;10(1):1333. doi: 10.1038/s41467-019-09307-6.

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

Author information

1
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 75013, Paris, France.
2
Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, 75006, Paris, France.
3
Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, 75000, Paris, France.
4
Service de Chirurgie Thoracique, Hôpital Calmette - CHRU de Lille, 59000, Lille, France.
5
Université de Lille, 59045, Lille, France.
6
Service de Chirurgie Générale et Thoracique, CHU de Rouen, 76000, Rouen, France.
7
Laboratoire de Biochimie (LBC), ESPCI Paris, PSL Research University, CNRS UMR8231 Chimie Biologie Innovation, 75005, Paris, France.
8
Translational Research Department, Institut Curie, PSL Research University, 75005, Paris, France.
9
Institut de Pathologie, Centre de Biologie-Pathologie, CHRU de Lille, 59037, Lille, France.
10
Laboratoire de Pathologie Clinique et Expérimentale (LPCE) et biobanque (BB-0033-00025), CHRU de Nice, 06003, Nice, France.
11
Université Côte d'Azur, 06108, Nice, France.
12
Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 75015, Paris, France.
13
Département de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 75015, Paris, France.
14
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, 75013, Paris, France. aurelien.dereynies@ligue-cancer.net.
15
Centre de Recherche des Cordeliers, Sorbonne Universités, Inserm, UMRS-1138, 75006, Paris, France. didier.jean@inserm.fr.
16
Functional Genomics of Solid Tumors, USPC, Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Immuno-Oncology, 75000, Paris, France. didier.jean@inserm.fr.

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.

PMID:
30902996
PMCID:
PMC6430832
DOI:
10.1038/s41467-019-09307-6
[Indexed for MEDLINE]
Free PMC Article

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