Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity

• Published in: Nature (London) Vol. 566; no. 7744; pp. 403 - 406
• Main Authors: Vriens, Kim, Christen, Stefan, Parik, Sweta, Broekaert, Dorien, Yoshinaga, Kazuaki, Talebi, Ali, Dehairs, Jonas, Escalona-Noguero, Carmen, Schmieder, Roberta, Cornfield, Thomas, Charlton, Catriona, Romero-Pérez, Laura, Rossi, Matteo, Rinaldi, Gianmarco, Orth, Martin F., Boon, Ruben, Kerstens, Axelle, Kwan, Suet Ying, Faubert, Brandon, Méndez-Lucas, Andrés, Kopitz, Charlotte C., Chen, Ting, Fernandez-Garcia, Juan, Duarte, João A. G., Schmitz, Arndt A., Steigemann, Patrick, Najimi, Mustapha, Hägebarth, Andrea, Van Ginderachter, Jo A., Sokal, Etienne, Gotoh, Naohiro, Wong, Kwok-Kin, Verfaillie, Catherine, Derua, Rita, Munck, Sebastian, Yuneva, Mariia, Beretta, Laura, DeBerardinis, Ralph J., Swinnen, Johannes V., Hodson, Leanne, Cassiman, David, Verslype, Chris, Christian, Sven, Grünewald, Sylvia, Grünewald, Thomas G. P., Fendt, Sarah-Maria
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 13/51; 38/77; 631/45/287/1183; 631/67/2327; 64/60; 692/308/2778; 692/699/67; 82/16; 82/58; 96/106; Animals; Apoptosis; Biosynthesis; Cancer; Cancer cells; Cancer research; Cell Line, Tumor; Cell Membrane - metabolism; Cell Proliferation; Desaturase; Desaturation; Fatty Acid Desaturases - metabolism; Fatty acid metabolism; Fatty acids; Fatty Acids - chemistry; Fatty Acids - metabolism; Female; Gene expression; HEK293 Cells; Hepatocellular carcinoma; Humanities and Social Sciences; Humans; Letter; Lipid metabolism; Lipids; Liver; Liver cancer; Lung cancer; Lung carcinoma; Male; Metabolic Networks and Pathways; Metabolism; Mice; multidisciplinary; Neoplasms - metabolism; Neoplasms - pathology; Neurophysiology; Oleic Acids - metabolism; Palmitates - metabolism; Palmitic acid; Palmitic Acids - metabolism; Physiological aspects; Plastic properties; Plasticity; Prostate; Science; Science (multidisciplinary); Stearoyl-CoA desaturase; Stearoyl-CoA Desaturase - metabolism; Tumor cell lines; Tumors
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-0904-1

Most tumours have an aberrantly activated lipid metabolism 1 , 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 desaturation 3 . 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. In several human and mouse cancer cell lines and carcinomas, a sapienate biosynthesis pathway underpins metabolic plasticity by allowing these cells to bypass stearoyl-CoA desaturase-dependent fatty acid desaturation.