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

Our plain-English summary of Combined deletion of Bap1, Nf2, and Cdkn2ab causes rapid onset of malignant mesothelioma in mice, by J. Badhai, G.K. Pandey, J.Y. Song, et al (The Journal of Experimental Medicine, 2020).

The study

• Authors: J. Badhai, G.K. Pandey, J.Y. Song, O. Krijgsman, R. Bhaskaran, G. Chandrasekaran, M.C. Kwon, L. Bombardelli, K. Monkhorst, C. Grasso, J. Zevenhoven, J. van der Vliet, M. Cozijnsen, P. Krimpenfort, D. Peeper, M. van Lohuizen, A. Berns
• Journal: The Journal of Experimental Medicine
• Published: 2020;217(6)
• Cited by: 47 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2020 Badhai et al.

In plain English

This was a laboratory study in genetically engineered mice. The authors used mice carrying conditional alleles of Bap1 and Nf2 together with Cdkn2ab mice that were germline deleted for Ink4a and Ink4b but conditional for p19Arf; the floxed alleles were deleted in the mesothelial lining of the chest by injecting an adenovirus carrying Cre recombinase into the pleural space. Combined loss of all three loci (BNC) produced malignant mesothelioma in all 18 mice, with a median survival of 85 days; mice with Nf2 and Cdkn2ab loss alone (NC) had a median survival of 190 days and developed mesothelioma in 75% of cases, while adding heterozygous Bap1 loss gave 140 days. Deleting Bap1 alone in 20 mice did not cause mesothelioma up to 700 days, apart from one heterozygous mouse. BNC tumours showed epithelioid, sarcomatoid and biphasic histology, MAPK and PI3K pathway activation, and an inflammatory immune infiltrate resembling that of asbestos-exposed human mesothelioma, although no asbestos was used. Cisplatin plus pemetrexed extended median survival from 61 to 84 days. The authors concluded the model is suited to studying mesothelioma pathogenesis and testing treatments.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: animal experiment using genetically engineered (conditional knockout) mouse models, with comparison to human mesothelioma tissue and public genomic data
• Who was studied: Cohorts of mice of mixed C57BL/6, FVB and 129Ola background carrying conditional alleles (BNC n=18; Bap1f/+;Nf2f/f;Cdkn2ab−/− n=8; NC n=17; BNCa n=13; NCa n=12; Bap1-only cohort n=20), plus tumour tissue from 12 selected mesothelioma patients at the Netherlands Cancer Institute
• Exposure: Genetic inactivation of Bap1, Nf2 and Cdkn2a/Cdkn2ab; Bap1 and Nf2 were conditional (Cre-induced in the pleural space), while the Cdkn2ab mice were germline deleted for Ink4a and Ink4b with only p19Arf conditional. No asbestos exposure. Drug exposures tested: cisplatin plus pemetrexed, PI3K inhibitor BEZ-235, PARP inhibition and gamma-radiation
• Main results:
  • All BNC mice developed mesothelioma; 75% of NC mice developed mesothelioma while 25% died of other tumours such as histiocytic sarcoma and lymphoma
  • Median survival was 190 days for NC mice, 140 days with heterozygous Bap1 loss and 85 days with homozygous Bap1 loss
  • Bap1 deletion alone did not produce mesothelioma in a cohort of 20 mice followed up to 700 days, except in one heterozygous floxed mouse
  • BNCa mice (Bap1, Nf2, Cdkn2a) had median survival of 114 days versus 244 days for NCa mice (Nf2, Cdkn2a)
  • In BNC tumour-bearing mice, cisplatin plus pemetrexed raised median survival to 84 days compared with 61 days in untreated mice
  • RNA sequencing of BNC (n=3) versus NC (n=3) tumour cell lines found 1,954 deregulated genes, 1,182 down-regulated and 772 up-regulated
  • H3K27me3 occupancy at promoter sites was 78% in BAP1-deficient cells versus 55% in BAP1-proficient cells
  • CIBERSORT analysis indicated M2 macrophages, T cells and B cells made up a major fraction of leukocytes in both BNC mouse tumours (n=5) and asbestos-exposed human mesotheliomas with BAP1, NF2 and CDKN2A alterations (n=6)
  • Bap1 deletion increased sensitivity of mesothelioma cells to gamma-radiation and PARP inhibition, while PI3K inhibition sensitivity was independent of BAP1 status
• The authors' conclusion: The authors concluded that their autochthonous mouse models, especially BNC, reproduce the fast-developing, inflammatory human disease and are suited to studying mesothelioma pathogenesis, chemotherapy resistance and new treatments including immunotherapy
• Limitations the authors state:
  • The authors stated it was unclear whether the biphasic tumours represent independently arisen epithelioid and sarcomatoid clones
  • The authors noted that BAP1 loss did not clearly increase genomic instability, so the mechanism of PARP inhibitor sensitivity remains unexplained
  • The authors noted the inflammatory immunophenotype was similar in BNC and NC mice and so is not specific to Bap1 loss

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: BAP1, Mesothelioma, Cisplatin, Pemetrexed (Alimta), Immunotherapy.

Related studies

• Fluorescence in situ hybridization (FISH) provides estimates of minute and interstitial BAP1, CDKN2A, and NF2 gene deletions in peritoneal mesothelioma — S. Brich, F. Bozzi, et al. (2020)
• Homozygous deletion of CDKN2A/2B is a hallmark of iron-induced high-grade rat mesothelioma — Q. Hu, S. Akatsuka, et al. (2010)
• Whole-exome sequencing reveals frequent genetic alterations in BAP1, NF2, CDKN2A, and CUL1 in malignant pleural mesothelioma — G. Guo, J. Chmielecki, et al. (2015)
• Sarcomatoid Mesothelioma: A CDKN2A molecular analysis of 53 cases with immunohistochemical correlation with BAP1 — M. Zaleski, N. Kalhor, et al. (2020)
• Frequent homozygous deletion of Cdkn2a/2b in tremolite-induced malignant mesothelioma in rats — Y. Okazaki, N. Misawa, et al. (2020)
• CDKN2A deletion is associated with immune desertification in diffuse pleural mesothelioma — F. Torricelli, B. Donati, et al. (2025)

Browse more research in The Journal of Experimental Medicine, or return to medical research.