PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers

Abstract : High-grade serous ovarian cancer (HGSOC) re- mains an unmet medical challenge. Here, we unravel an unanticipated metabolic heterogene- ity in HGSOC. By combining proteomic, metabo- lomic, and bioergenetic analyses, we identify two molecular subgroups, low- and high-OXPHOS. While low-OXPHOS exhibit a glycolytic meta- bolism, high-OXPHOS HGSOCs rely on oxidative phosphorylation, supported by glutamine and fatty acid oxidation, and show chronic oxidative stress. We identify an important role for the PML-PGC-1a axis in the metabolic features of high-OXPHOS HGSOC. In high-OXPHOS tumors, chronic oxidative stress promotes aggregation of PML-nuclear bodies, resulting in activation of the transcriptional co-activator PGC-1a. Active PGC-1a increases synthesis of electron trans- port chain complexes, thereby promoting mito- chondrial respiration. Importantly, high-OXPHOS HGSOCs exhibit increased response to conven- tional chemotherapies, in which increased oxida- tive stress, PML, and potentially ferroptosis play key functions. Collectively, our data establish a stress-mediated PML-PGC-1a-dependent mecha- nism that promotes OXPHOS metabolism and che- mosensitivity in ovarian cancer.