Significance: Millions of people have been exposed to asbestos and are at increased risk of developing mesothelioma, an aggressive malignancy resistant to current therapies. Here, we elucidate critical steps in asbestos carcinogenesis: asbestos induces the release of high mobility group box 1 that triggers autophagy. Autophagy activation constitutes a key biological process that allows some mesothelial cells to survive asbestos cytotoxicity and consequently increases the fraction of DNA-damaged human mesothelial cells susceptible to malignant transformation. We found that the inhibition of autophagy using either chloroquine or the antidepressant drug desmethylclomipramine increased asbestos-induced cell death and reduced asbestos-mediated cell transformation. Our data suggest that these Food and Drug Administration-approved drugs might be repurposed to protect high-risk asbestos-exposed individuals from developing mesothelioma.

CD44, a cell surface glycoprotein, has been increasingly implicated in the pathogenesis and progression of epithelial ovarian cancer, the deadliest gynecologic malignancy in women. Here, we review recent reports on the expression and function of CD44 in epithelial ovarian carcinoma. Further functional data for CD44 in peritoneal adhesion and metastatic progression and its association with stem cells is highlighted. Recent studies utilizing CD44 for therapeutic targeting are also discussed.

Significance: We found that the probability of carrying heterozygous germline BLM mutations is significantly higher among mesothelioma patients than in the general population. In vitro and in vivo experiments suggest that heterozygous BLM mutations increase susceptibility to mesothelioma. BLM -mutation carriers are at higher risk of developing mesothelioma, and their risk increases upon asbestos exposure. Therefore, BLM mutation carriers should benefit from prevention and screening for early detection. We suggest that genetic testing to identify carriers of BLM heterozygous mutations and genetic counseling would help identify individuals at higher risk of mesothelioma and provide mutation carriers the option to implement simple preventive measures to reduce exposure to asbestos and other carcinogenic fibers to decrease their risk of developing mesothelioma.

BAP1 is a powerful tumor suppressor gene characterized by haplo insufficiency. Individuals carrying germline BAP1 mutations often develop mesothelioma, an aggressive malignancy of the serosal layers covering the lungs, pericardium, and abdominal cavity. Intriguingly, mesotheliomas developing in carriers of germline BAP1 mutations are less aggressive, and these patients have significantly improved survival. We investigated the apparent paradox of a tumor suppressor gene that, when mutated, causes less aggressive mesotheliomas. We discovered that mesothelioma biopsies with biallelic BAP1 mutations showed loss of nuclear HIF-1α staining. We demonstrated that during hypoxia, BAP1 binds, deubiquitylates, and stabilizes HIF-1α, the master regulator of the hypoxia response and tumor cell invasion. Moreover, primary cells from individuals carrying germline BAP1 mutations and primary cells in which BAP1 was silenced using siRNA had reduced HIF-1α protein levels in hypoxia. Computational modeling and co-immunoprecipitation experiments revealed that mutations of BAP1 residues I675, F678, I679, and L691 -encompassing the C-terminal domain-nuclear localization signal- to A, abolished the interaction with HIF-1α. We found that BAP1 binds to the N-terminal region of HIF-1α, where HIF-1α binds DNA and dimerizes with HIF-1β forming the heterodimeric transactivating complex HIF. Our data identify BAP1 as a key positive regulator of HIF-1α in hypoxia. We propose that the significant reduction of HIF-1α activity in mesothelioma cells carrying biallelic BAP1 mutations, accompanied by the significant reduction of HIF-1α activity in hypoxic tissues containing germline BAP1 mutations, contributes to the reduced aggressiveness and improved survival of mesotheliomas developing in carriers of germline BAP1 mutations.

Significance: Our findings explain mechanistically the observed gene × environment (G×E) interaction in mesotheliomas occurring in carriers of heterozygous germline BAP1 mutations ( BAP1 ^+/− ) exposed to asbestos. The increased amount of acetylated HMGB1 can be measured in the serum and may prove useful as a diagnostic/prognostic biomarker of mesothelioma in BAP1 ^+/− individuals. Inhibition of HMGB1 secretion in Bap1 ^+/− mutant mice exposed to asbestos significantly decreased the incidence of mesothelioma and prolonged the survival of those who developed mesothelioma. This strategy may be translated to carriers of germline BAP1 mutations with the aim of decreasing their incidence of mesothelioma.