FADS2-mediated fatty acid desaturation and cholesterol esterification are signatures of metabolic reprogramming during melanoma progression

Identifying metabolic alterations in disease progression has been challenged by difficulties in tracking metabolites at sub-cellular level. Here, by high-resolution stimulated Raman scattering and pump-probe imaging and spectral phasor analysis of melanoma cells grouped by MITF/AXL expression pattern and of human patient tissues paired by primary and metastatic status, we identify a metabolic switch from a pigment-containing phenotype in low-grade melanoma to a lipid-rich phenotype in metastatic melanoma. The lipids found in MITFlow/AXLhigh melanoma cells contain high levels of cholesteryl ester (CE) and unsaturated fatty acid species. Elevated fatty acid uptake activity in MITFlow/AXLhigh melanoma contributes to the lipid-rich phenotype, and inhibiting fatty acid uptake suppresses cell migration. Importantly, monounsaturated sapienate is identified as an essential fatty acid that effectively promotes cancer migration. Blocking either FADS2-mediated lipid desaturation or SOAT-mediated cholesterol esterification effectively suppresses the migration capacity of melanoma in vitro and in vivo, indicating the therapeutic potential of targeting these metabolic pathways in metastatic melanoma. Collectively, our results reveal metabolic reprogramming during melanoma progression, and highlight metabolic signatures that could serve as targets for metastatic melanoma treatment and diagnosis.