Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice

We have generated mouse models of malignant mesothelioma (MM) based upon disruption of the Bap1, Nf2, and Cdkn2ab tumor suppressor loci in various combinations as also frequently observed in human MM. Inactivation of all three loci in the mesothelial lining of the thoracic cavity leads to a highly a...

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Podrobná bibliografie
Vydáno v:	The Journal of experimental medicine Ročník 217; číslo 6
Hlavní autoři:	Badhai, Jitendra, Pandey, Gaurav Kumar, Song, Ji-Ying, Krijgsman, Oscar, Bhaskaran, Rajith, Chandrasekaran, Gayathri, Kwon, Min-Chul, Bombardelli, Lorenzo, Monkhorst, Kim, Grasso, Cristoforo, Zevenhoven, John, van der Vliet, Jan, Cozijnsen, Miranda, Krimpenfort, Paul, Peeper, Daniel, van Lohuizen, Maarten, Berns, Anton
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.06.2020
Témata:	Animals Cyclin-Dependent Kinase Inhibitor p15 - metabolism Cyclin-Dependent Kinase Inhibitor p16 - metabolism Disease Models, Animal Disease Progression Gene Deletion Humans Immunophenotyping MAP Kinase Signaling System - drug effects Mesothelioma, Malignant - genetics Mesothelioma, Malignant - metabolism Mesothelioma, Malignant - pathology Mice Neurofibromin 2 - metabolism Phosphatidylinositol 3-Kinases - metabolism Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Protein Kinase Inhibitors - pharmacology Transcription, Genetic - drug effects Tumor Microenvironment - drug effects Tumor Suppressor Proteins - metabolism Ubiquitin Thiolesterase - metabolism
ISSN:	1540-9538, 1540-9538
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Popis
Shrnutí:	We have generated mouse models of malignant mesothelioma (MM) based upon disruption of the Bap1, Nf2, and Cdkn2ab tumor suppressor loci in various combinations as also frequently observed in human MM. Inactivation of all three loci in the mesothelial lining of the thoracic cavity leads to a highly aggressive MM that recapitulates the histological features and gene expression profile observed in human patients. The tumors also show a similar inflammatory phenotype. Bap1 deletion alone does not cause MM but dramatically accelerates MM development when combined with Nf2 and Cdkn2ab (hereafter BNC) disruption. The accelerated tumor development is accompanied by increased Polycomb repression and EZH2-mediated redistribution of H3K27me3 toward promoter sites with concomitant activation of PI3K and MAPK pathways. Treatment of BNC tumor-bearing mice with cisplatin and pemetrexed, the current frontline treatment, prolongs survival. This makes the autochthonous mouse model described here very well suited to explore the pathogenesis of MM and validate new treatment regimens for MM, including immunotherapy.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1540-9538 1540-9538
DOI:	10.1084/jem.20191257