Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity

Abstract

Most tumors have an aberrantly activated lipid metabolism 1 , 2 , which enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive toward approaches targeting fatty acid metabolism, and in particular fatty acid desaturation 3 . This suggests that many cancer cells harbor an unexplored plasticity in their fatty acid metabolism. Here, we discover that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, murine hepatocellular carcinomas (HCC), and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known stearoyl-CoA desaturase (SCD)-dependent fatty acid desaturation. Thus, only by targeting both desaturation pathways the in vitro and in vivo proliferation of sapienate synthesizing cancer cells is impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

“…This protective effect of exogenous MUFAs requires free fatty acid activation by ACSL3, suggesting that competition between ACSL4‐driven incorporation of highly oxidizable PUFAs versus ACSL3‐driven incorporation of less oxidizable MUFAs into phospholipids shapes the sensitivity of the plasma membrane to oxidation. A different enzyme, fatty acid desaturase 2 (FADS2), which converts the saturated fatty acid palmitate (C16:0) to the MUFA sapienate ( cis ‐6‐C16:1), can potentially promote ferroptosis sensitivity by limiting the incorporation of other protective MUFAs into membrane phospholipids . Further investigation is required to understand how different MUFAs modulate ferroptosis sensitivity.…”

Cell density-dependent ferroptosis in breast cancer is induced by accumulation of polyunsaturated fatty acid-enriched triacylglycerides

“…For each sample, the area of fatty acid metabolites was subsequently normalized to the protein content and to the C17 internal standard area. With the setup used, cis-C18:1 isomers like oleate and cis-8-octadecenoate cannot be separated 58 . However, since cis-8-octadecenoate is an elongation product of sapienate and sapienate is very low 58 , we assumed that the cis8/9-C18:1 peak only represents oleate.…”

“…With the setup used, cis-C18:1 isomers like oleate and cis-8-octadecenoate cannot be separated 58 . However, since cis-8-octadecenoate is an elongation product of sapienate and sapienate is very low 58 , we assumed that the cis8/9-C18:1 peak only represents oleate. A Matlab M-file was also used to perform an isotopomer spectral analysis (ISA) 59 to determine the fraction of newly synthesized palmitate, stearate and oleate.…”

Adaptive response to BET inhibition induces therapeutic vulnerability to MCL1 inhibitors in breast cancer

“…For example, high mesenchymal cell states are resistant to diverse therapies, at least in part, stemming from their dependence on lipid peroxidase pathways, and as a result converging on the actionable GPX4 enzyme (45). The compensatory and alternating roles of SCD and FADS2 enzymes in regulating fatty acid desaturation are further evidence for the interplay between cellular plasticity and lipid metabolism (46). Here, for the first time, we linked epigenetic targeting to cellular and signaling plasticity and their consequential drug escape, which can be overcome with the combination of BET and MCL1 inhibition.…”