KRAS signaling in malignant pleural mesothelioma

Our plain-English summary of KRAS signaling in malignant pleural mesothelioma, by A. Marazioti, A.C. Krontira, S.J. Behrend, et al (EMBO Molecular Medicine, 2022).

The study

• Authors: A. Marazioti, A.C. Krontira, S.J. Behrend, G.A. Giotopoulou, G. Ntaliarda, C. Blanquart, H. Bayram, M. Iliopoulou, M. Vreka, L. Trassl, M.A.A. Pepe, C.M. Hackl, L.V. Klotz, S.A.I. Weiss, I. Koch, M. Lindner, R.A. Hatz, J. Behr, D.E. Wagner, H. Papadaki, S.G. Antimisiaris, D. Jean, S. Deshayes, M. Grégoire, Ö. Kayalar, D. Mortazavi, Ş. Dilege, S. Tanju, S. Erus, Ö. Yavuz, P. Bulutay, P. Fırat, I. Psallidas, M. Spella, I. Giopanou, I. Lilis, A.S. Lamort, G.T. Stathopoulos
• Journal: EMBO Molecular Medicine
• Published: 2022;14(2):e13631
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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 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.

© 2021 The Authors. Published under the terms of the CC BY 4.0 license.

In plain English

This laboratory study examined whether KRAS alterations contribute to malignant pleural mesothelioma (MPM), described by the authors as mainly caused by inhaled asbestos. The authors curated mutation data from COSMIC and 10 published MPM studies, one of them the TCGA pan-cancer dataset (86 patients), which they analysed in detail; they also tested effusions from 45 Munich patients (12 with MPM) and 17 Istanbul MPM tumours by digital droplet PCR, and 33 Nantes MPM cell lines by microarray and targeted sequencing. In the TCGA set, KRAS alteration alone was found in 10 patients (12%) and combined KRAS/TP53 alteration in 7 (8%); KRAS-altered patients showed more biphasic histology and worse survival. In mice, Cre-mediated KRASG12D expression in the pleural mesothelium produced epithelioid MPM (median survival 339 days, 95% CI 285 to 379), while added biallelic Trp53 deletion produced biphasic MPM with effusions (41 days, 95% CI 38 to 73); control and Trp53-deleted mice showed no disease up to 16 months. Three derived cell lines were transplantable; one intrapleural dose of liposomal deltarasin in mice bearing KPM1 tumours gave fewer, smaller effusions with reduced cellularity at day 19.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Combined human genomic/molecular analysis of public datasets and patient samples plus genetically engineered mouse experiments and cell-line work
• Who was studied: Public datasets (COSMIC n=775; 10 studies n=838, including the TCGA pan-cancer MPM dataset n=86 patients analysed in detail); 45 patients with pleural effusion from Munich (12 with MPM); 33 primary MPM cell lines and effusion samples from Nantes; 17 MPM tumour samples from Istanbul; one MAPED patient from Patras; and mice (total n=432, C57BL/6 background)
• Exposure: In humans, KRAS and TP53 mutations/copy number alterations in MPM; in mice, Cre-induced expression of oncogenic KRASG12D with or without Trp53 deletion targeted to the pleural or peritoneal mesothelium by adenoviral vector
• Main results:
  • TCGA pan-cancer MPM dataset: KRAS alteration alone in 10 patients (12%), combined KRAS/TP53 alteration in 7 (8%), total KRAS alteration rate 20%
  • TCGA patients were stratified into KRAS standalone (n = 10) and combined KRAS/TP53 (n = 7) altered groups
  • Among TCGA patients, those with KRAS alterations showed more biphasic histology and worse survival; KRAS and TP53 alterations co-occurred no more than expected by chance, and repulsion of NF2 mutations was not significant
  • Munich cohort: 3 of 12 MPM patients had standalone KRAS mutations and 2 of 12 had combined KRAS/TP53 alterations
  • Nantes cell lines: standalone KRAS alterations in 9 and combined KRAS/TP53 alterations in 5 of 33 primary MPM cell lines
  • Across the authors' own cohorts, low allelic frequency KRAS mutations were found in 50% of MPM samples
  • Wild-type, Trp53f/Wt and Trp53f/f mice survived up to 16 months after Ad-Cre without clinical or pathologic disease
  • Mice with mesothelial KRASG12D alone developed epithelioid MPM with median survival 339 days (95% CI 285-379), P = 0.005 versus controls
  • Mice with KRASG12D plus biallelic Trp53 deletion died with biphasic MPM and pleural effusions, median survival 41 days (95% CI 38-73), P less than 0.001 versus any other genotype
  • KRASG12D;Trp53f/Wt mice showed an intermediate phenotype with median survival 118 days (95% CI 97-160)
  • Mouse MPM (KPM) cell lines carried multiple secondary Bap1 variants, though nuclear BAP1 protein remained detectable
  • In mice bearing pleural KPM1 tumours only, one intrapleural dose of liposomal deltarasin reduced effusion number and size, measured at day 19
• The authors' conclusion: The authors concluded that KRAS mutations play a pathogenic role in a fraction of MPM and that their mouse models provide new tools for studying this subgroup
• Limitations the authors state:
  • The authors state their human findings await validation in larger cohorts
  • The functional significance of the Bap1 mutations found in the mouse cell lines was uncertain because BAP1 protein was still expressed
  • Whether KRAS mutations are early events in MPM was a postulation left for future testing

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelial Cells, Pleural Cavity, BAP1, CDKN2A, Mesothelium, Epithelioid, Biphasic Mesothelioma.

Related studies

• Driver Gene and Novel Mutations in Asbestos-Exposed Lung Adenocarcinoma and Malignant Mesothelioma Detected by Exome Sequencing — S. Mäki-Nevala, V.K. Sarhadi, et al. (2016)
• Immunohistochemical staining of ras oncogene product in neoplastic and non-neoplastic mesothelial tissues: immunoreactivity for N-ras and lack of immunohistochemical staining for Ha-ras and K-ras — M. Ramael, I. Deblier, et al. (1993)
• KRAS Pathway Alterations in Malignant Pleural Mesothelioma: An Underestimated Player — L. Trassl, G.T. Stathopoulos (2022)
• Correlation between serum oncogene protein expression and the development of neoplastic disease in a worker exposed to carcinogens — P.W. Brandt-Rauf, H.L. Niman, et al. (1990)
• Endogenous retrovirus expression activates type-I interferon signaling in an experimental mouse model of mesothelioma development — S. Sun, F. Frontini, et al. (2021)
• Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas — E. Sementino, C.W. Menges, et al. (2018)

Browse return to medical research.