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Supplemental Fig. 3 from Inactivation of Bap1 Cooperates with Losses of Nf2 and Cdkn2a to Drive the Development of Pleural Malignant Mesothelioma in Conditional Mouse Models

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posted on 2023-03-31, 02:22 authored by Anna-Mariya Kukuyan, Eleonora Sementino, Yuwaraj Kadariya, Craig W. Menges, Mitchell Cheung, Yinfei Tan, Kathy Q. Cai, Michael J. Slifker, Suraj Peri, Andres J. Klein-Szanto, Frank J. Rauscher, Joseph R. Testa

RT-PCR analysis was performed on 13 of 16 PRC2 target genes indicated in the heatmap derived from the RNA-seq analysis of genes differentially expressed between malignant mesotheliomas (MMs) from Nf2;Cdkn2a double-CKO mice and Bap1;Nf2;Cdkn2a triple-CKO mice (Figure 6B). Four genes upregulated in MMs from Bap1;Nf2;Cdkn2a triple-CKO mice validated by RT-PCR are presented here, and 3 other genes up- or downregulated in these tumors are shown in Figure 6C.

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Pleural malignant mesothelioma is a therapy-resistant cancer affecting the serosal lining of the thoracic cavity. Mutations/deletions of BAP1, CDKN2A, and NF2 are the most frequent genetic lesions in human malignant mesothelioma. We introduced various combinations of these deletions in the pleura of conditional knockout (CKO) mice, focusing on the contribution of Bap1 loss. While homozygous CKO of Bap1, Cdkn2a, or Nf2 alone gave rise to few or no malignant mesotheliomas, inactivation of Bap1 cooperated with loss of either Nf2 or Cdkn2a to drive development of malignant mesothelioma in approximately 20% of double-CKO mice, and a high incidence (22/26, 85%) of malignant mesotheliomas was observed in Bap1;Nf2;Cdkn2a (triple)-CKO mice. Malignant mesothelioma onset was rapid in triple-CKO mice, with a median survival of only 12 weeks, and malignant mesotheliomas from these mice were consistently high-grade and invasive. Adenoviral-Cre treatment of normal mesothelial cells from Bap1;Nf2;Cdkn2a CKO mice, but not from mice with knockout of one or any two of these genes, resulted in robust spheroid formation in vitro, suggesting that mesothelial cells from Bap1;Nf2;Cdkn2a mice have stem cell–like potential. RNA-seq analysis of malignant mesotheliomas from triple-CKO mice revealed enrichment of genes transcriptionally regulated by the polycomb repressive complex 2 (PRC2) and others previously implicated in known Bap1-related cellular processes. These data demonstrate that somatic inactivation of Bap1, Nf2, and Cdkn2a results in rapid, aggressive malignant mesotheliomas, and that deletion of Bap1 contributes to tumor development, in part, by loss of PRC2-mediated repression of tumorigenic target genes and by acquisition of stem cell potential, suggesting a potential avenue for therapeutic intervention. Combinatorial deletions of Bap1, Nf2, and Cdkn2a result in aggressive mesotheliomas, with Bap1 loss contributing to tumorigenesis by circumventing PRC2-mediated repression of oncogenic target genes.

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