Metastatic cancer cells exhibit distinct metabolic adaptations, not observed in the primary tumor, facilitating their survival and proliferation in the new conditions of the distant site. Notably, certain nutrients present in the new organ aid metastatic cells in spreading and colonizing by activating metabolic and signaling pathways. For example, recently, we elucidated how disseminated breast cancer cells (DBCs) utilize the fatty acid (FA) palmitate present in the lung milieu, through mitochondrial oxidation to activate a pro-metastatic signaling cascade via protein acetylation. Inhibiting this utilization of palmitate by blocking FA oxidation significantly reduced lung metastasis formation. Intriguingly, in contrast, we discovered that DBCs undergoing a state of dormancy in lungs do not rely on exogenous palmitate and hence do not respond to FA uptake inhibition. Instead, we found that dormant DBCs upregulate de novo lipogenesis, rerouting glucose-derived carbons toward FA synthesis. Mechanistically, this metabolic shift favors the activation and incorporation of monounsaturated fatty acids (MUFAs) into cellular membranes through the activation of acyl-coenzyme-A synthetase long-chain-family-member 3 (ACSL3), conferring protection against lipid peroxidation and ferroptosis. Blocking both lipogenesis or ACSL3 in dormant DBCs resulted in a shift from MUFA to polyunsaturated-enriched lipid profiles, accumulation of lipid peroxides and increased cell death. Notably, inhibition of lipogenesis or ACSL3 impaired the survival of dormant DBCs in vivo and decreased the formation of micrometastases in the lungs. Clinically, ACSL3 was found to be overexpressed in quiescent DBCs in the lymph nodes of breast cancer patients and to significantly correlate with shorter disease-free and overall survival. Collectively, our findings provide new insights into the molecular mechanisms underpinning the survival of dormant DBCs and highlight the therapeutic potential of targeting the diverse roles of FAs in the metastatic cascade.

Trabajo presentado en European Association for Cancer Research (EACR) Cancer Metabolism, celebrada en Bilbao (España), del 8 al 10 de octubre de 2024