Asbestos exposure induces malignant-like phenotypes via minority MOMP and displays characteristics of drug-tolerant persister cells

Pleural mesothelioma usually occurs many years after asbestos fiber exposure; yet the mechanisms that convert chronic damage into malignancy remain unclear. Asbestos fibers induce persistent oxidative and genomic stress that should activate apoptosis via mitochondrial outer membrane permeabilization (MOMP). MOMP normally triggers cytochrome c (cyt c) release as well as mitochondrially derived damage-associated molecular patterns, resulting in downstream caspase activation, which leads to DNA damage and cell death. With sublethal activation, a phenomenon known as an "incomplete or minority MOMP (mMOMP)" occurs in which the cell survives the damage, enabling retention and propagation of somatic mutations. We tested whether prolonged asbestos fiber exposure drives mMOMP in the mesothelial cells, MeT-5A. After culturing the cells for 6 months with chrysotile asbestos fibers or crocidolite asbestos fibers, we observed an increase in clonogenicity, migration, and invasion, suggesting that transformation to a malignant-like phenotype was occurring. Next, we found increases in reactive oxygen species (ROS) production, cyt c release, and γH2AX phosphorylation without activation of caspase-3 and apoptotic induction. These cellular features are consistent with mMOMP. Additionally, an anti-apoptotic, mitochondrial protein, myeloid cell leukemia-1 was upregulated by asbestos and enabled mMOMP by preventing MOMP. Furthermore, we observed that asbestos-induced mMOMP was associated with features of drug-tolerant persister cells. mMOMP facilitates avoidance of apoptosis by mesothelial cells while acquiring malignant traits. Our study indicates that mMOMP is a mechanism that promotes carcinogenesis, mitochondrial changes, and metabolic reprogramming. These findings offer a foundation for future therapeutic investigations.