Most tumours have an aberrantly activated lipid metabolism1,2 that enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive to approaches that target fatty acid metabolism and, in particular, fatty acid desaturation3. This suggests that many cancer cells contain an unexplored plasticity in their fatty acid metabolism. Here we show that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, mouse hepatocellular carcinomas, 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 fatty acid desaturation pathway that is dependent on stearoyl-CoA desaturase. Thus, only by targeting both desaturation pathways is the in vitro and in vivo proliferation of cancer cells that synthesize sapienate impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.
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The authors declare that all data supporting the findings of this study are available within the article, its Extended Data, Source Data or from the corresponding author upon reasonable request.
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We thank all patients and volunteers as well as J. van Pelt, I. Vander Elst and P. Windmolders for advice on the orthotopic injections and patient sample collection; F. Impens and D. Van Haver (VIB Proteomics Core); V. van Hoef (VIB-CCB Bioinformatics Expertise Center); and D. Nittner (VIB-CCB Histology Expertise Center). S.P. is supported by a VIB International PhD student fellowship. G.R. is supported by Kom op tegen Kanker and FWO fellowships. R.S., M.R., J.F.-G. and J.A.G.D. are supported by FWO fellowships. R.J.D., a Howard Hughes Medical Institute Investigator, Joel B. Steinberg, M.D. Chair in Pediatrics and Robert L. Moody, Sr. Faculty Scholar at UT Southwestern, are funded by CPRIT (RP160089) and the National Cancer Institute (R35CA22044901). T.G.P.G. is funded by the German Cancer Aid (DKH-111886, DKH-70112257), LMUexcellent, Bettina-Bräu-Stiftung, Dr. Leopold und Carmen Ellinger, Matthias-Lackas, Walter Schulz, Wilhelm Sander (2016.167.1), Gert & Susanna Mayer Foundations, and the Deutsche Forschungsgemeinschaft (DFG 391665916). S.-M.F. is funded by the European Research Council under the ERC Consolidator Grant Agreement n.771486–MetaRegulation and Marie Curie CIG n.617727–MetabolismConnect, FWO Odysseus II, KU Leuven Methusalem Co-funding, and Bayer AG.
Nature thanks Andrew Hoy, Almut Schulze and the other anonymous reviewer(s) for their contribution to the peer review of this work.