EMBO Molecular Medicine (Feb 2022)
KRAS signaling in malignant pleural mesothelioma
- 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
Affiliations
- Antonia Marazioti
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Anthi C Krontira
- Laboratory for Molecular Respiratory Carcinogenesis Department of Physiology Faculty of Medicine University of Patras Rio Greece
- Sabine J Behrend
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Georgia A Giotopoulou
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Giannoula Ntaliarda
- Laboratory for Molecular Respiratory Carcinogenesis Department of Physiology Faculty of Medicine University of Patras Rio Greece
- Christophe Blanquart
- Université de Nantes CNRS INSERM CRCINA Nantes France
- Hasan Bayram
- Department of Pulmonary Medicine Koc University School of Medicine Istanbul Turkey
- Marianthi Iliopoulou
- Laboratory for Molecular Respiratory Carcinogenesis Department of Physiology Faculty of Medicine University of Patras Rio Greece
- Malamati Vreka
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Lilith Trassl
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Mario A A Pepe
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Caroline M Hackl
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Laura V Klotz
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Stefanie A I Weiss
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Ina Koch
- German Center for Lung Research (DZL) Gießen Germany
- Michael Lindner
- German Center for Lung Research (DZL) Gießen Germany
- Rudolph A Hatz
- German Center for Lung Research (DZL) Gießen Germany
- Juergen Behr
- German Center for Lung Research (DZL) Gießen Germany
- Darcy E Wagner
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Helen Papadaki
- Department of Anatomy Faculty of Medicine University of Patras Rio Greece
- Sophia G Antimisiaris
- Laboratory for Pharmaceutical Technology Department of Pharmacy School of Health Sciences University of Patras Rio Greece
- Didier Jean
- Centre de Recherche des Cordeliers INSERM Sorbonne Université Université de Paris Functional Genomics of Solid Tumors Paris France
- Sophie Deshayes
- Université de Nantes CNRS INSERM CRCINA Nantes France
- Marc Grégoire
- Université de Nantes CNRS INSERM CRCINA Nantes France
- Özgecan Kayalar
- Koc University Research Center for Translational Medicine (KUTTAM) Koc University School of Medicine Istanbul Turkey
- Deniz Mortazavi
- Koc University Research Center for Translational Medicine (KUTTAM) Koc University School of Medicine Istanbul Turkey
- Şükrü Dilege
- Department of Thoracic Surgery Koc University School of Medicine Istanbul Turkey
- Serhan Tanju
- Department of Thoracic Surgery Koc University School of Medicine Istanbul Turkey
- Suat Erus
- Department of Thoracic Surgery Koc University School of Medicine Istanbul Turkey
- Ömer Yavuz
- Department of Thoracic Surgery Koc University School of Medicine Istanbul Turkey
- Pınar Bulutay
- Department of Pathology Koc University School of Medicine Istanbul Turkey
- Pınar Fırat
- Department of Pathology Koc University School of Medicine Istanbul Turkey
- Ioannis Psallidas
- Laboratory for Molecular Respiratory Carcinogenesis Department of Physiology Faculty of Medicine University of Patras Rio Greece
- Magda Spella
- Laboratory for Molecular Respiratory Carcinogenesis Department of Physiology Faculty of Medicine University of Patras Rio Greece
- Ioanna Giopanou
- Laboratory for Molecular Respiratory Carcinogenesis Department of Physiology Faculty of Medicine University of Patras Rio Greece
- Ioannis Lilis
- Laboratory for Molecular Respiratory Carcinogenesis Department of Physiology Faculty of Medicine University of Patras Rio Greece
- Anne‐Sophie Lamort
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- Georgios T Stathopoulos
- Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD) Helmholtz Center Munich‐German Research Center for Environmental Health (HMGU) and Ludwig‐Maximilian‐University (LMU) Munich Munich Germany
- DOI
- https://doi.org/10.15252/emmm.202013631
- Journal volume & issue
-
Vol. 14,
no. 2
pp. n/a – n/a
Abstract
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.
Keywords