Abstract B103: Statins decrease mesothelial clearance, an early step in ovarian cancer metastasis

Abstract

Abstract Ovarian cancer has a low 5-year survival rate often associated with detection of late-stage cancer due to the difficulty of early detection. Ovarian cancer metastasis can occur via a distinct mechanism compared to other solid cancers. Ovarian cancer spheroids slough off from the primary tumor. In the ascites, these spheroids attach to and clear the protective layer of mesothelial cells that line the peritoneum. Once this mesothelial clearance occurs, the ovarian spheroids can invade the connective tissue and metastasize to further parts of the body or grow implanted in the peritoneum. Targeting mesothelial clearance may be a new mechanism to treat ovarian cancer. Previously, it was shown that the use of statins, drugs commonly used to control cholesterol, is associated with decreased ovarian cancer occurrence. In addition, statins have the potential to interfere with several signaling pathways that are known to play key roles in cancer including metastasis. The potential for statins to target metastasis could be beneficial in treating cancers like ovarian cancer that tend to be found in metastatic stages. Therefore, we hypothesized that statins would reduce mesothelial clearance by ovarian cancer spheroids. Using an in vitro mesothelial clearance assay, we have found that statins, such as simvastatin and lovastatin, decrease the mesothelial clearing abilities of ovarian cancer spheroids. To better understand the mechanism of mesothelial clearance inhibition, we analyzed several known downstream pathways. Targeting HMGCR by siRNA, the known molecular target of statins, reduced mesothelial clearance. In addition, targeting Rac1 and CDC42 using the inhibitor AZA1 has a similar inhibitory effect as simvastatin on mesothelial clearance. This suggests that inhibition of Rac1 by statins may be the mechanism that statins inhibit mesothelial clearance. To support this, siRNA knockdown of RAC1 suggests the importance of Rac1 for mesothelial clearance. Previously, we found that treatment of ovarian spheroids with geranylgeranyl-pyrophosphate partially rescued the inhibition of viability by statins. Therefore, our current working hypothesis is that statins disrupt the function of Rac1 by reducing the cellular supply of geranylgeranyl-pyrophosphate through inhibiting HMGCR and the mevalonate pathway. While we are currently further analyzing the mechanisms behind this pathway, we believe this evidence suggests an exciting new therapeutic route for treating ovarian cancer. Citation Format: Brendan M Reilly, Olivia R Martin, Allison F Mackey, Sarah R Walker. Statins decrease mesothelial clearance, an early step in ovarian cancer metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B103.