KRAS signaling in malignant pleural mesothelioma

Autor: Antonia Marazioti, Anthi C Krontira, Sabine J Behrend, Georgia A Giotopoulou, Giannoula Ntaliarda, Christophe Blanquart, Hasan Bayram, Marianthi Iliopoulou, Malamati Vreka, Lilith Trassl, Mario A A Pepe, Caroline M Hackl, Laura V Klotz, Stefanie A I Weiss, Ina Koch, Michael Lindner, Rudolph A Hatz, Juergen Behr, Darcy E Wagner, Helen Papadaki, Sophia G Antimisiaris, Didier Jean, Sophie Deshayes, Marc Grégoire, Özgecan Kayalar, Deniz Mortazavi, Şükrü Dilege, Serhan Tanju, Suat Erus, Ömer Yavuz, Pınar Bulutay, Pınar Fırat, Ioannis Psallidas, Magda Spella, Ioanna Giopanou, Ioannis Lilis, Anne‐Sophie Lamort, Georgios T Stathopoulos
Přispěvatelé: Ludwig Maximilian University [Munich] (LMU), University of Patras [Patras], German Center for Lung Research, Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Koç University, Asklepios Klinikum Uckermark GmbH, Lund University [Lund], Institute of Chemical Engineering and High Temperature Chemical Processes, (FORTH/ICE-HT), Foundation for Research and Technology - Hellas (FORTH), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), University of Patras, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Bernardo, Elizabeth, Bayram, Hasan (ORCID 0000-0002-5236-766X & YÖK ID 4890), Dilege, Mustafa Şükrü (ORCID 0000-0002-1071-5291 & YÖK ID 122573), Tanju, Serhan (ORCID 0000-0002-2363-233X & YÖK ID 214690), Erus, Suat (ORCID 0000-0002-6162-3266 & YÖK ID 175565), Yavuz, Ömer, Bulutay, Pınar (ORCID 0000-0001-5497-1513 & YÖK ID 133565), Fırat, Pınar Arıkan (ORCID 0000-0001-8340-2678 & YÖK ID 207545), Marazioti, Antonia, Krontira, Anthi C., Behrend, Sabine J., Giotopoulou, Georgia A., Ntaliarda, Giannoula, Blanquart, Christophe, Iliopoulou, Marianthi, Vreka, Malamati, Trassl, Lilith, Pepe, Mario A. A., Hackl, Caroline M., Klotz, Laura, V, Weiss, Stefanie A., I, Koch, Ina, Lindner, Michael, Hatz, Rudolph A., Behr, Juergen, Wagner, Darcy E., Papadaki, Helen, Antimisiaris, Sophia G., Jean, Didier, Deshayes, Sophie, Gregoire, Marc, Kayalar, Özgecan, Mortazavi, Deniz, Psallidas, Ioannis, Spella, Magda, Giopanou, Ioanna, Lilis, Ioannis, Lamort, Anne-Sophie, Stathopoulos, Georgios T., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: EMBO Mol. Med.:e13631 (2021)
EMBO Molecular Medicine
EMBO Molecular Medicine, Wiley Open Access, 2021, pp.e13631. ⟨10.15252/emmm.202013631⟩
EMBO Molecular Medicine, 2021, pp.e13631. ⟨10.15252/emmm.202013631⟩
EMBO Molecular Medicine, Vol 14, Iss 2, Pp n/a-n/a (2022)
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202013631⟩
Popis: 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.
European Union (EU); Horizon 2020; European Research Council 2010 Starting Independent Investigator; ERC Proof of Concept 2015 (ERC-PoC-2015); German Research Society; ALTERNATIVE; German Ministry for Education and Research; German Center for Lung Research Translational Research Grant; Greek State Scholarship Foundation Program; European Union (EU); European Union Social Fund; Greek National Fund; Reinforcement of Postdoctoral Researchers-1 stand 2nd cycles; General Secretariat for Research and Innovation; Hellenic Foundation for Research and Innovation; REPSIRE European Respiratory Society Fellowship; Institut National de la Sante et de la Recherche Medicale (INSERM); Centre National de la Recherche Scientifique (CNRS); Institut de Recherche en Sante Respiratoire des Pays de la Loire; National Research Agency Programme d' Investissements d' Avenir; Pays de la Loire Region Research Program; Ligue Contrele Cancer; Chancellerie des Universites de Paris; Projekt DEAL
Databáze: OpenAIRE
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