SCD1/FADS2 and ferroptosis signalings orchestrate ovarian cancer cell metabolism and metastatic progression in peritoneal metastases

Abstract

Peritoneal metastases are common and usually associated with poor prognosis in advanced ovarian cancers. Emerging evidence indicates that the ascites microenvironment provides a key reservoir of growth factors and free fatty acids for promoting metastatic recurrence and chemoresistance of ovarian cancers. However, how the metastatic ovarian cancer cells adapt and utilize such a unique tumor microenvironment remains elusive. Here, we report that ovarian cancer cells co-cultured in ascites or omental conditioned medium (OCM) enhance their oncogenic capacities through elevated lipid metabolism. RNA sequencing (RNA-seq) and lipidomic profiling analyses revealed two key mediators of UFAs; Stearoyl-CoA Desaturase-1 (SCD1) and Fatty acid Desaturase-2 (FADS2) were upregulated accompanied with the accumulation of poly- and mono-unsaturated fatty acids (UFAs) in ovarian cancer cells co-cultured in OCM. Enforced expression of either SCD1 or FADS2 promotes cancer stemness, in vitro and ex vivo tumor colony formation, and cell migration/invasion through activation of NFκB signaling. SCD1/FADS2 increases not only UFAs accumulation but also the cell membrane fluidity, which is crucial for the epithelial-mesenchymal transition (EMT) and metastatic potentials. On the other hand, RNA-Seq analysis of SCD1/FADS2-depleted ovarian cancer cells showed the ferroptotic activities were inversely correlated with SCD1/FADS2. Of note, either knockout of SCD1/FADS2 or co-treatment of Erastin could enhance cisplatin-induced cytotoxicity through the elevation of iron-mediated reactive oxygen species (ROS), and subsequently led ferroptosis by downregulation of GPX4/xCT expressions in ovarian cancer cells. Higher tumorigenic capacity is expressed in iron-rich ovarian cancer cells, which contains sphere formation, EMT potential, and cell viability. Taken together, SCD1/FADS2 and ferroptosis signaling pathways orchestrate the metabolic activities, ROS stresses, and cellular iron homeostasis during the metastatic progression of ovarian cancer cells in the peritoneum microenvironment. Hence, targeting these signaling cascades by the drug cocktail/combination strategy could reduce the risk of metastatic recurrence and chemoresistance in advanced ovarian cancers.