Targeting mitochondrial adaptations to suppress metastatic outgrowth in serous ovarian cancer

PROJECT SUMMARY Serous ovarian cancer is the 5th leading cause of cancer-related deaths in women, with a 30% survival rate when spread into the highly hypoxic and visceral peritoneal cavity.

Despite efforts to treat this highly metastatic disease, traditional chemotherapeutic and cytoreductive therapies are unable to diminish or induce cell death of circulating metastases from colonizing secondary sites due to their genetic and histologic heterogeneity.

The dissemination route for primary metastasis, however, is most often conserved to the peritoneal cavity, which is low in nutrients and hypoxic (1-2% O2).

Cells exfoliated from the primary tumor will aggregate during migration, which elicits a survival signal to maintain viability in this environment. The underlying cellular and molecular changes involved with aggregation has yet to be determined.

We have previously found that aggregation of murine ovarian surface epithelial (MOSE) cells present a more suppressed metabolic phenotype upon aggregation accompanied by an increase in localized mitochondrial fragmentation.

My proposed research seeks to identify a phenotypic switch from enhanced mitophagy during peritoneal dissemination that supports survival of ovarian cancer cell aggregates to mitochondrial biogenesis during secondary tissue colonization that enables proliferation.

I will use a syngeneic murine model of progressive ovarian cancer grown in physiologically relevant conditions to characterize changes in mitochondrial dynamics during aggregation, adhesion and secondary outgrowth.

I then will use specific inhibitors to block the reversibility of these changes to confirm their relevance for tumor outgrowth in vitro and in vivo.

This proposed research will contribute to understanding the role of mitophagy as a survival rather than apoptotic signal in cancer cells as adaptation to nutrient-deprived environments, while also identifying how these processes can be reversed to support invasion and metastatic capacity during secondary colonization.

This proposal is significant because it will identify molecular adaptations associated with the viability of disseminating cancer metastases as well as promote novel preventative therapeutics that can be used to limit the mortality of highly aggressive ovarian cancer in women.