Abstract A12: Regulation of the mitochondrial stress response and metabolism by the intraperitoneal tumor environment during ovarian cancer transcoelomic metastasis
Authors: Shin Dong-Hui , Jones Victoria , Shimko Sara , Dier Usawadee , Shepherd Trevor , Patrick Timmins , Hempel Nadine 
Published: May 2019

Transcoelomic metastasis represents one of the routes by which ovarian cancer cells colonize the omental tissues of the intraperitoneal (IP) cavity. Large quantities of viable tumor cells and spheroid aggregates can be isolated from ascites of advanced stage ovarian cancer patients, suggesting that cancer cells spend some time in anchorage independence under the physical and chemical influence of the IP tumor environment. Using ovarian cancer cell lines and patient ascites-derived tumor cells we demonstrate that levels of the mitochondrial stress response proteins, superoxide dismutase 2 (Sod2) and the deacetylase sirtuin 3 (SIRT3), are significantly increased when cultured in anchorage independent conditions, where cells rapidly form spheroid aggregates. Mimicking the ascites fluid current we show that expression of these proteins is further enhanced when spheroids are exposed to sheer forces, suggesting that the physical environment influences cellular stress adaptation. Presently, the combination of these physical cues and chemical stimuli emanating from ascites fluid are being interrogated in the co-regulation of the above mitochondrial proteins, focusing on the role of redox modulators and metabolite composition of ascites. It is our hypothesis that this stress response adaptation not only aids survival of cells in anchorage independence, but that it also drives a metabolic regulatory switch. Anchorage independent spheroids display a slowing in glycolysis and an increase in mitochondrial respiratory reserve capacity, as assessed by extracellular flux analysis. Sod2 expression is required for maintaining this mitochondrial respiratory function by scavenging damaging superoxide anion. Further, we observe decreases in global and mitochondrial acetylation, suggesting that deacetylase activity may be increased in spheroids. SIRT3 is a direct regulator of Sod2 activity, and is an important sensor of nutrient stress and modulator of metabolism, including the stimulation of fatty acid oxidation by deacetylation and activation of long-chain-specific acyl-CoA dehydrogenase. It has previously been demonstrated that metastatic ovarian cancer cells rely on fatty acid oxidation given their propensity to colonize the lipid-rich environments of the omentum. Studies are under way to test the hypothesis that SIRT3 expression stimulated by the IP tumor environment during anchorage independence primes ovarian cancer cells for fatty acid oxidation and is a necessary step before the colonization of the omentum.

Citation Format: Dong-Hui Shin, Victoria Jones, Sara Shimko, Usawadee Dier, Trevor Shepherd, Timmins Patrick, Nadine Hempel. Regulation of the mitochondrial stress response and metabolism by the intraperitoneal tumor environment during ovarian cancer transcoelomic metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A12.