KRAS signaling in malignant pleural mesothelioma.

Autor: Marazioti A; 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.; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece., Krontira AC; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece., Behrend SJ; 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.; German Center for Lung Research (DZL), Gießen, Germany., Giotopoulou GA; 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.; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.; German Center for Lung Research (DZL), Gießen, Germany., Ntaliarda G; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece., Blanquart C; Université de Nantes, CNRS, INSERM, CRCINA, Nantes, France., Bayram H; Department of Pulmonary Medicine, Koc University School of Medicine, Istanbul, Turkey.; Koc University Research Center for Translational Medicine (KUTTAM), Koc University School of Medicine, Istanbul, Turkey., Iliopoulou M; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece., Vreka M; 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.; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.; German Center for Lung Research (DZL), Gießen, Germany., Trassl L; 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.; German Center for Lung Research (DZL), Gießen, Germany., Pepe MAA; 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.; German Center for Lung Research (DZL), Gießen, Germany., Hackl CM; 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.; German Center for Lung Research (DZL), Gießen, Germany., Klotz LV; 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.; German Center for Lung Research (DZL), Gießen, Germany., Weiss SAI; 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.; German Center for Lung Research (DZL), Gießen, Germany., Koch I; German Center for Lung Research (DZL), Gießen, Germany.; Center for Thoracic Surgery Munich, Ludwig-Maximilian-University (LMU) Munich and Asklepios Medical Center, Gauting, Germany., Lindner M; German Center for Lung Research (DZL), Gießen, Germany.; Center for Thoracic Surgery Munich, Ludwig-Maximilian-University (LMU) Munich and Asklepios Medical Center, Gauting, Germany., Hatz RA; German Center for Lung Research (DZL), Gießen, Germany.; Center for Thoracic Surgery Munich, Ludwig-Maximilian-University (LMU) Munich and Asklepios Medical Center, Gauting, Germany., Behr J; German Center for Lung Research (DZL), Gießen, Germany.; Department of Medicine V, University Hospital, Ludwig-Maximilian-University (LMU) Munich, Munich, Germany., Wagner DE; 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.; German Center for Lung Research (DZL), Gießen, Germany.; Lung Bioengineering and Regeneration, Department of Experimental Medical Sciences, Lund Stem Cell Center, Wallenberg Molecular Medicine Center, Faculty of Medicine, Lund University, Lund, Sweden., Papadaki H; Department of Anatomy, Faculty of Medicine, University of Patras, Rio, Greece., Antimisiaris SG; Laboratory for Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, Rio, Greece.; Foundation for Research and Technology Hellas, Institute of Chemical Engineering, FORTH/ICE-HT, Rio, Greece., Jean D; Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Functional Genomics of Solid Tumors, Paris, France., Deshayes S; Université de Nantes, CNRS, INSERM, CRCINA, Nantes, France., Grégoire M; Université de Nantes, CNRS, INSERM, CRCINA, Nantes, France., Kayalar Ö; Koc University Research Center for Translational Medicine (KUTTAM), Koc University School of Medicine, Istanbul, Turkey., Mortazavi D; Koc University Research Center for Translational Medicine (KUTTAM), Koc University School of Medicine, Istanbul, Turkey., Dilege Ş; Department of Thoracic Surgery, Koc University School of Medicine, Istanbul, Turkey., Tanju S; Department of Thoracic Surgery, Koc University School of Medicine, Istanbul, Turkey., Erus S; Department of Thoracic Surgery, Koc University School of Medicine, Istanbul, Turkey., Yavuz Ö; Department of Thoracic Surgery, Koc University School of Medicine, Istanbul, Turkey., Bulutay P; Department of Pathology, Koc University School of Medicine, Istanbul, Turkey., Fırat P; Department of Pathology, Koc University School of Medicine, Istanbul, Turkey., Psallidas I; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece., Spella M; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece., Giopanou I; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece., Lilis I; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece., Lamort AS; 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.; German Center for Lung Research (DZL), Gießen, Germany., Stathopoulos GT; 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.; Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece.; German Center for Lung Research (DZL), Gießen, Germany.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2022 Feb 07; Vol. 14 (2), pp. e13631. Date of Electronic Publication: 2021 Dec 13.
DOI: 10.15252/emmm.202013631
Abstrakt: 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.
(© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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