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Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity

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journal contribution
posted on 19.12.2019 by Kim Vriens, Stefan Christen, Sweta Parik, Dorien Broekaert, Kazuaki Yoshinaga, Ali Talebi, Jonas Dehairs, Carmen Escalona-Noguero, Roberta Schmieder, Thomas Cornfield, Catriona Charlton, Laura Romero-Pérez, Matteo Rossi, Gianmarco Rinaldi, Martin F Orth, Ruben Boon, Axelle Kerstens, Suet Ying Kwan, Brandon Faubert, Andrés Méndez-Lucas, Charlotte C Kopitz, Ting Chen, Juan Fernandez-Garcia, João AG Duarte, Arndt A Schmitz, Patrick Steigemann, Mustapha Najimi, Andrea Hägebarth, Jo A Van Ginderachter, Etienne Sokal, Naohiro Gotoh, Kwok-Kin Wong, Catherine Verfaillie, Rita Derua, Sebastian Munck, Mariia Yuneva, Laura Beretta, Ralph J DeBerardinis, Johannes V Swinnen, Leanne Hodson, David Cassiman, Chris Verslype, Sven Christian, Sylvia Grünewald, Thomas GP Grünewald, Sarah-Maria Fendt
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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