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KRAS signaling in malignant pleural mesothelioma

Marazioti, Antonia ; Krontira, Anthi C ; Behrend, Sabine J ; Giotopoulou, Georgia A ; Ntaliarda, Giannoula ; Blanquart, Christophe ; Bayram, Hasan ; Iliopoulou, Marianthi ; Vreka, Malamati and Trassl, Lilith , et al. (2022) In EMBO Molecular Medicine 14(2).
Abstract

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural... (More)

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.

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type
Contribution to journal
publication status
published
subject
in
EMBO Molecular Medicine
volume
14
issue
2
publisher
Wiley-Blackwell
external identifiers
  • scopus:85121047603
  • pmid:34898002
ISSN
1757-4684
DOI
10.15252/emmm.202013631
language
English
LU publication?
yes
additional info
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
id
370b8b19-d1b2-4970-b24c-ff9660a18547
date added to LUP
2021-12-20 19:29:32
date last changed
2025-03-24 02:30:29
@article{370b8b19-d1b2-4970-b24c-ff9660a18547,
  abstract     = {{<p>Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.</p>}},
  author       = {{Marazioti, Antonia and Krontira, Anthi C and Behrend, Sabine J and Giotopoulou, Georgia A and Ntaliarda, Giannoula and Blanquart, Christophe and Bayram, Hasan and Iliopoulou, Marianthi and Vreka, Malamati and Trassl, Lilith and Pepe, Mario A A and Hackl, Caroline M and Klotz, Laura V and Weiss, Stefanie A I and Koch, Ina and Lindner, Michael and Hatz, Rudolph A and Behr, Juergen and Wagner, Darcy E and Papadaki, Helen and Antimisiaris, Sophia G and Jean, Didier and Deshayes, Sophie and Grégoire, Marc and Kayalar, Özgecan and Mortazavi, Deniz and Dilege, Şükrü and Tanju, Serhan and Erus, Suat and Yavuz, Ömer and Bulutay, Pınar and Fırat, Pınar and Psallidas, Ioannis and Spella, Magda and Giopanou, Ioanna and Lilis, Ioannis and Lamort, Anne-Sophie and Stathopoulos, Georgios T}},
  issn         = {{1757-4684}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{EMBO Molecular Medicine}},
  title        = {{KRAS signaling in malignant pleural mesothelioma}},
  url          = {{http://dx.doi.org/10.15252/emmm.202013631}},
  doi          = {{10.15252/emmm.202013631}},
  volume       = {{14}},
  year         = {{2022}},
}