The roles of DGAT2 in promoting omental metastasis of ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is one of the fatal gynecological malignancies around the globe, accounting for over 90% of ovarian cancer cases. Most patients with EOC are defectively diagnosed at advanced stages accompanied with severe omental metastasis and peritoneal dissemination, leading to a typically poor prognosis and aggressive tumor recurrence from minimal residual disease (MRD). Mounting evidence from different groups and our team has disclosed that lipid-enriched ascitic/omental microenvironments provide surplus free fatty acids for sustaining ovarian tumor growth, rendering omentum as a preferential site for ovarian cancer carcinomatosis. Therefore, understanding the molecular mechanisms associated with the stimulatory effects of the omental metastatic niche on ovarian cancer cell growth and aggressiveness is of great importance to speed up the development of novel therapeutic strategies against transcoelomic metastasis of ovarian cancer. In this study, transcriptomic analysis, QPCR analysis and IHC analysis were assessed on specimens of omental metastatic lesions of EOC and the corresponding pair of primary tumors. DGAT2 was consistently found to be highly upregulated in the omental metastatic tumors, while DGAT1 was relatively less obvious in expression status in both primary and metastatic counterparts, implying that DGAT2 was clinically relevant to take the leading role in directing EOC carcinomatosis. Kaplan-Meier survival analysis furthermore unveiled a more favorable prognosis in EOC patients with low DGAT2 expression when compared with the high expression group, inferring a reciprocal correlation between DGAT2 level and long-term survival among ovarian cancer patients. Exploiting omental conditioned medium (OCM) to mimics the ascitic/omental microenvironment, pharmaceutical inhibition or genetic silencing of DGAT2 significantly reduced OCM-initiated lipid droplets formation, ATP production, cell proliferation and cell migration/invasion, while accelerating the capacity of ROS stress in human ovarian cancer cell lines and primary culture of ascites-derived ovarian cancer cells. Rescue experiments with overexpression of DGAT2 in OCM-cocultured ovarian cancer cells showed increased cell proliferation and cell migration/invasion, enhanced accumulation of lipid droplets in the cytoplasmic compartment and augmented tumor colonization in ex vivo murine omental-tumor model, supporting that the upregulated DGAT2 enhanced lipid metabolic activities, proliferation and aggression of ovarian cancer cells in omental tumor microenvironment (TME). Mechanistic studies demonstrated that the inhibition of DGAT2 reduced expression of phospho-AKT and phosphor-mTOR, indicating that DGAT2 functioned as AKT upstream in promoting cancer cells growth and metastasis through activating AKT/mTOR signaling cascade. Further investigations revealed that pharmaceutical inhibition or genetic deletion of DGAT2 sensitized RSL3-induced ferroptosis in in vitro OCM-cocultured ovarian cancer cells and in vivo tumor dissemination. Meanwhile, inhibition of DGAT2 led to downregulation of two ferroptosis executioners, ACSL4 and LPCAT3. These findings not only revealed that DGAT2 augmented tumor aggressiveness of ovarian cancer cells, but also suggested the utility of combining DGAT2 inhibitors with ferroptosis inducers as a potential target-based therapy in eradicating peritoneal metastases of EOC. Thus, findings herein shed light on the orchestrated action of DGAT2 inhibitors and combined ferroptosis initiating therapies (FITs) in enhancing therapeutic outcomes of metastatic ovarian cancer and benefiting EOC patients with peritoneal metastases.