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

Abstract

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.

New understandings of the pathway of long-chain polyunsaturated fatty acid biosynthesis

“…These results were paralleled in primary liver cancer samples and in lung cancer tissue samples compared to adjacent noncancer tissue [18 & ]. Similarly, in metastatic melanoma, increased FADS2 expression caused synthesis of 16:1n-10, reported in a 2020 preprint [32]. 16:1n-10 synthesis in human skin is facilitated by low SCD (catalyzing 18:0!18:1n-9 and 16:0!16:1n-7) and high FADS2 expression; rodent skin expresses Scd and does not synthesize appreciable 16:1n-10.…”

Oxidative stress mediates the inhibitory effects of Manzamine A on uterine leiomyoma cell proliferation and extracellular matrix deposition via SOAT inhibition

“…Depleting CEs by SOAT inhibition downregulated the wingless-type (WNT)/β-catenin pathway in cancers through reduced acylation of WNTs [ 38 , 39 ]. Therefore, we determine whether Manz A interrupts the downstream signaling of SOAT, the β-catenin pathway.…”

“…This SOAT/β-catenin/ECM proteins axis might align with aberrant lipid metabolism. SOAT inhibition decreased the number of lipid droplets, alleviating the monounsaturated FA to serve as substrates for WNT protein acylation, weakening the β-catenin signaling [ 38 , 39 ]. Suppressing cholesterol esterification by SOAT inhibition blocks secretion of Wnt3a by reducing levels for Wnt3a acylation [ 39 ].…”

Identification of Long Noncoding RNAs Involved in Eyelid Pigmentation of Hereford Cattle

“…The CXCL13 gene encodes a homeostatic chemokine that traffics B cells and is involved in the immune response ( Müller et al, 2002 ). Fatty acid transporters, such as FABP4, were recently shown to increase their expression during metastatic melanoma development, suggesting a higher uptake of fatty acids and metabolic reprogramming that serves as a signature for this condition ( Lee et al, 2020 ). In contrast, the lncRNAs TCONS_00109545 and TCONS_00078693 showed upregulated expression in the pigmented samples.…”