Multi-site tumor sampling highlights molecular intra-tumor heterogeneity in malignant pleural mesothelioma.
IF: 15.266
Cited by: 26


Malignant pleural mesothelioma (MPM) is a heterogeneous cancer. Better knowledge of molecular and cellular intra-tumor heterogeneity throughout the thoracic cavity is required to develop efficient therapies. This study focuses on molecular intra-tumor heterogeneity using the largest series to date in MPM and is the first to report on the multi-omics profiling of a substantial series of multi-site tumor samples. Intra-tumor heterogeneity was investigated in 16 patients from whom biopsies were taken at distinct anatomical sites. The paired biopsies collected from apex, side wall, costo-diaphragmatic, or highest metabolic sites as well as 5 derived cell lines were screened using targeted sequencing. Whole exome sequencing, RNA sequencing, and DNA methylation were performed on a subset of the cohort for deep characterization. Molecular classification, recently defined histo-molecular gradients, and cell populations of the tumor microenvironment were assessed. Sequencing analysis identified heterogeneous variants notably in NF2, a key tumor suppressor gene of mesothelial carcinogenesis. Subclonal tumor populations were shared among paired biopsies, suggesting a polyclonal dissemination of the tumor. Transcriptome analysis highlighted dysregulation of cell adhesion and extracellular matrix pathways, linked to changes in histo-molecular gradient proportions between anatomic sites. Methylome analysis revealed the contribution of epigenetic mechanisms in two patients. Finally, significant changes in the expression of immune mediators and genes related to immunological synapse, as well as differential infiltration of immune populations in the tumor environment, were observed and led to a switch from a hot to a cold immune profile in three patients. This comprehensive analysis reveals patient-dependent spatial intra-tumor heterogeneity at the genetic, transcriptomic, and epigenetic levels and in the immune landscape of the tumor microenvironment. Results support the need for multi-sampling for the implementation of molecular-based precision medicine.


Spatial Transcriptomics
NF2 subclonal mutation
Spatial molecular intra-tumor heterogeneity
Thoracic tumor
Tumor microenvironment


Meiller, Clément
Montagne, François
Hirsch, Theo Z
Caruso, Stefano
de Wolf, Julien
Bayard, Quentin
Assié, Jean-Baptiste
Meunier, Léa
Blum, Yuna
Quetel, Lisa
Gibault, Laure
Pintilie, Ecaterina
Badoual, Cécile
Humez, Sarah
Galateau-Sallé, Françoise
Copin, Marie-Christine
Letouzé, Eric
Scherpereel, Arnaud
Zucman-Rossi, Jessica
Le Pimpec-Barthes, Françoise
Jaurand, Marie-Claude
Jean, Didier

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