MITOCHONDRIAL STRESS RESPONSE ADAPTATIONS ARE REQUIRED FOR OVARIAN CANCER ANCHORAGE-INDEPENDENT SURVIVAL AND METASTASIS

Late stage ovarian cancer is marked by poor patient survival and significant metastatic spread throughout the peritoneal cavity. During transcoelomic spread cells must adapt to survive anchorage-independence and to cope with stress associated with matrix detachment and the hostile environment of the ascites. Our findings demonstrate that an important ovarian cancer cell adaptation during anchorage-independence is the up-regulation of the mitochondrial stress response proteins, the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2), and it9s regulator, the nutrient and redox sensing deacetylase SIRT3. We show that these proteins are necessary for anchorage-independent cell survival and transcoelomic metastasis in vivo. In addition to Sod29s role as a mitochondrial superoxide scavenger, mechanistic data show that Sod2 shifts the redox landscape of cancer cells to a higher hydrogen peroxide (H2O2) steady-state. This novel non-canonical function of Sod2 results in H2O2-dependent oxidation and inactivation of phosphatases, including PTEN. Sod2/H2O2-dependent redox signaling may hence be a novel driver of anchorage-independent survival and an important contributor to the high frequency of Akt activation observed in metastatic ovarian cancers. While these sub-lethal increases in cellular H2O2 lead to pro-tumorigenic signaling, this also places cells closer to the cytotoxic threshold of H2O2, making cells with high Sod2 expression exquisitely sensitive to exogenous H2O2 application, and H2O2 generating agents, including high dose ascorbate. These findings provide an important clue to the vulnerability of Sod2 expressing cancer cells. Our findings also demonstrate that SIRT3 is an important regulator of Sod2 activity during anchorage-independence, which challenges previous studies demonstrating that SIRT3 is a tumor suppressor, and points to a novel pro-survival role for SIRT3 during ovarian cancer spread. Given that SIRT3 is sensitive to nutrient stress, this regulation has further consequences on the ability of ovarian cancer cells to survive potentially nutrient deprived tumor environments. Our study has identified two important mitochondrial stress response genes that are specifically increased in response to matrix detachment and required for anchorage independent survival and metastatic spread of ovarian cancer. Our ongoing studies are investigating their role in the context of redox and nutrient stress of ascites and targeting these stress adaptations for therapeutic intervention. Citation Format: Piyushi Gupta-Vallur, Yeon Soo Kim, Dong-Hui Shin, LP Madhubhani Hemachandra, Rebecca Phaeton, Karthikeyan Mythreye, and Nadine Hempel. MITOCHONDRIAL STRESS RESPONSE ADAPTATIONS ARE REQUIRED FOR OVARIAN CANCER ANCHORAGE-INDEPENDENT SURVIVAL AND METASTASIS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-029.