Peritoneal Spread of Ovarian Cancer harbors Therapeutic Vulnerabilities Regulated by FOXM1 and EGFR/ERBB2 Signaling

Peritoneal spread is the primary mechanism of metastasis of ovarian cancer, and survival of ovarian cancer cells in the peritoneal cavity as non-adherent spheroids and their adherence to the mesothelium of distant organs lead to cancer progression, metastasis and mortality. However, the mechanisms that govern this metastatic process in ovarian cancer cells remain poorly understood. In this study, we cultured ovarian cancer cell lines in adherent (AD) and in non-adherent (NAD) conditions in vitro and analyzed changes in mRNA and protein levels to identify mechanisms of tumor cell survival and proliferation in AD and NAD cells. EGFR or ERBB2 upregulated ZEB1 in NAD cells, which caused resistance to cell death and increased tumor-initiating capacity. Conversely, Forkhead box M1 (FOXM1) was required for the induction of Integrin Beta 1 (ITGB1), Integrin-α V (ITGAV), and Integrin-α 5 (ITGA5) for adhesion of cancer cells. FOXM1 also upregulated ZEB1, which could act as a feedback inhibitor of FOXM1 and caused the transition of AD cells to NAD cells. Strikingly, the combinatorial treatment with Lapatinib (dual kinase inhibitor of EGFR (ERBB1) and ERBB2) and Thiostrepton (FOXM1 inhibitor) reduced growth and peritoneal spread of ovarian cancer cells more effectively than either single agent treatment in vivo. In conclusion, these results demonstrate that FOXM1 and EGFR/ERBB2 pathways are key points of vulnerability for therapy to disrupt peritoneal spread and adhesion of ovarian cancer cells.