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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cluster Analysis
  • Epigenesis, Genetic / drug effects
  • Female
  • Genetic Heterogeneity* / drug effects
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology*
  • Male
  • Mesothelioma / drug therapy
  • Mesothelioma / genetics*
  • Mesothelioma / immunology
  • Mesothelioma / pathology*
  • Middle Aged
  • Pleural Neoplasms / drug therapy
  • Pleural Neoplasms / genetics*
  • Pleural Neoplasms / immunology
  • Pleural Neoplasms / pathology*
  • Prognosis
  • Young Adult

Substances

  • Antineoplastic Agents

Supplementary concepts

  • Mesothelioma, Malignant