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

Jitendra Badhai, Gaurav Kumar Pandey, Ji Ying Song, Oscar Krijgsman, Rajith Bhaskaran, Gayathri Chandrasekaran, Min Chul Kwon, Lorenzo Bombardelli, Kim Monkhorst, Cristoforo Grasso, John Zevenhoven, Jan van der Vliet, Miranda Cozijnsen, Paul Krimpenfort, Daniel Peeper, Maarten van Lohuizen, Anton Berns

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere20191257
JournalJournal of Experimental Medicine
Volume217
Issue number6
DOIs
StatePublished - 1 Jun 2020
Externally publishedYes

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