Targeting endogenous fatty acid synthesis stimulates the migration of ovarian cancer cells to adipocytes and promotes the transport of fatty acids from adipocytes to cancer cells

Abstract

Despite significant advances in oncology, 1 of 108 female patients succumb to ovarian cancer (OC) each year. Improved novel treatments against this aggressive disease would be a major improvement. The growth of OC cells has been demonstrated to be highly dependent on lipids. OC cells are abundantly present in the abdominal cavity and omentum, the main sites of OC expansion. Accordingly, it has been attempted not only to block the hyperactive synthesis of fatty acids (FAs) in cancer cells, but also to disrupt lipid supply. While either strategy has yielded promising results as monotherapy, the induction of resistance pathways diminishing the anticancer effects is yet conceivable. The endogenous regulation of lipid biosynthesis in OC has been extensively studied. However, the role of stromal cells in the modulation of the effects of anti-lipogenic drugs has not yet been well documented. The present study thus examined the interaction between OC cells and associated stromal cells, when de novo FA synthesis was blocked. It has recently been revealed by the authors that when FA are provided to OC cells in monoculture, the lipid deficiency induced by pharmacological inhibition of FA synthase (FASN), the key enzyme of endogenous FA synthesis, cannot be compensated through an increased FA uptake by OC cells. In the present study, OC cells were co-cultured with adipocytes preloaded with fluorescent FA and the effects of FASN-inhibition on OC homing to adipocytes and the transcellular delivery of fluorescent FA from adipocytes to OC cells were examined. The FASN inhibitors, G28UCM and Fasnall, stimulated the spontaneous migration of A2780 OC cells in a concentration-dependent manner and stimulated the transfer of FA from adipocytes to OC cells. Similar effects were observed with all types of adipocytes tested. The models applied in the present study demonstrated that co-cultured cancer-associated adipocytes may attenuate the anticancer effects of FASN inhibitors by attracting tumor cells and by supplying the cells with FA. This lipid-mediated dependency may provide a rationale for the design of new treatment approaches for the treatment of OC.

Unraveling the intricate relationship between lipid metabolism and oncogenic signaling pathways

“…Cancer-associated adipocytes serve as a significant supplier of external lipids for cancer cells. Research has shown a metabolic interaction between adipocytes and cancer cells, which causes the cancer cells to exhibit an aggressive phenotype ( Mukherjee et al, 2022 ; Grunt et al, 2024 ). Cancer cells stimulate the release of FAs from nearby adipocytes through the secretion of soluble substances, including hormone-sensitive lipase and growth differentiation factor 15 (GDF15) ( Bouche and Quail, 2023 ).…”