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Marazioti, A. ; Krontira, A.C.* ; Behrend, S.J. ; Giotopoulou, G.A. ; Ntaliarda, G.* ; Blanquart, C.* ; Bayram, H.* ; Iliopoulou, M.* ; Vreka, M. ; Trassl, L. ; Pepe, M. ; Hackl, C.M. ; Klotz, L.V. ; Weiss, S.A. ; Koch, I.* ; Lindner, M.* ; Hatz, R.A.* ; Behr, J. ; Wagner, D.E. ; Papadaki, H.* ; Antimisiaris, S.G.* ; Jean, D.* ; Deshayes, S.* ; Grégoire, M.* ; Kayalar,* ; Mortazavi, D.* ; Dilege,* ; Tanju, S.* ; Erus, S.* ; Yavuz, Ö.* ; Bulutay, P.* ; Fırat, P.* ; Psallidas, I.* ; Spella, M.* ; Giopanou, I.* ; Lilis, I.* ; Lamort, A.-S. ; Stathopoulos, G.T.

KRAS signaling in malignant pleural mesothelioma.

EMBO Mol. Med.:e13631 (2021)

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	Open Access Gold

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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 KRAS^G12D 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 KRAS^G12D 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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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Bap1 ; Kras ; Nf2 ; Tp53 ; Asbestos; Mouse Model; Iaslc Mesothelioma; Mutation Analysis; Carbon Nanotubes; Advanced-stage; Cancer Genes; Lung-cancer; Tnm Stage; In-vitro; Effusion

ISSN (print) / ISBN 1757-4676

e-ISSN 1757-4684

Journal EMBO Molecular Medicine

Quellenangaben Article Number: e13631

Publisher Wiley

Publishing Place Chichester

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Lung Health and Immunity (LHI)

Grants European Respiratory Society (ERS)
Institut National de la Santé et de la Recherche Médicale (Inserm)
Deutsche Forschungsgemeinschaft (DFG)
Bundesministerium fur Bildung und Forschung (BMBF)
Deutsches Zentrum fuer Lungenforschung
Pays de la Loire Region research program
National Research Agency under the Programme d'Investissements d'Avenir
INSERM, CNRS, the "Institut de Recherche en Santé Respiratoire des Pays de la Loire"
INSERM, the Ligue Contre le Cancer (Ile de France committee), and the Chancellerie des Universités de Paris (Legs POIX)
Greek State Scholarship Foundation Program 'Reinforcement of Postdoctoral Researchers-1st and 2nd cycles' co-financed by the European Union Social Fund and Greek national funds
Greek State Scholarship Foundation