Ovarian cancer remains a deadly disease in part due to ovarian cancer metastasis. Spheroids, clusters of ovarian cancer cells, interact and clear the protective mesothelial layer that lines the peritoneum in the early stages of ovarian cancer metastasis. There is a gap in knowledge regarding the signaling pathways and genes involved in mesothelial clearance. By not knowing these pathways, this may affect the ability to design drugs to target ovarian cancer metastasis. The STAT3 signaling pathway plays a role in mesothelial clearance. However, it is not known how the interaction of ovarian spheroids with mesothelial cells affects STAT3 activation in ovarian cancer cells. Endometriosis, a benign disease that may promote infertility and increase risk for ovarian cancer, has some similarities to ovarian cancer as the endometrioid cells also interact with the mesothelial cells, and STAT3 activation is elevated in patients with endometriosis. Statins, inhibitors of HMGCR, are often used to lower cholesterol; however, there is evidence that statins also inhibit STAT3. The long-term objective of this work is to develop drugs for the treatment of metastatic ovarian cancer. The central hypothesis is that interaction with mesothelial cells modulates STAT3 activity that can be attenuated with statin treatment. Aim 1 will determine the effects of interacting with mesothelial cells on STAT3 activation and define the mechanism of STAT3 inhibition by statins. Aim 2 will determine STAT3 target gene expression changes during mesothelial clearance that are blocked by statin treatment using single cell RNA-seq. Ovarian cancer cells will be compared to endometrioid cells to potentially identify cancer specific STAT3 target genes. Overall, the outcomes of the proposed work may provide a more complete understanding of the role of STAT3 in ovarian cancer metastasis and provide insight into the role of STAT3 in endometriosis, two gynecologic diseases that may greatly impact women across their lifespan.
