Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity

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 A. G. Duarte, Arndt A. Schmitz, Patrick Steigemann, Mustapha Najimi, Andrea Hägebarth, Jo A. 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 G. P. Grünewald and Sarah-Maria Fendt ()
Additional contact information
Kim Vriens: VIB-KU Leuven Center for Cancer Biology, VIB
Stefan Christen: VIB-KU Leuven Center for Cancer Biology, VIB
Sweta Parik: VIB-KU Leuven Center for Cancer Biology, VIB
Dorien Broekaert: VIB-KU Leuven Center for Cancer Biology, VIB
Kazuaki Yoshinaga: Tsukishima Foods Industry
Ali Talebi: Leuven Cancer Institute (LKI)
Jonas Dehairs: Leuven Cancer Institute (LKI)
Carmen Escalona-Noguero: VIB-KU Leuven Center for Cancer Biology, VIB
Roberta Schmieder: VIB-KU Leuven Center for Cancer Biology, VIB
Thomas Cornfield: University of Oxford, Churchill Hospital
Catriona Charlton: University of Oxford, Churchill Hospital
Laura Romero-Pérez: Institute of Pathology, Faculty of Medicine, LMU Munich
Matteo Rossi: VIB-KU Leuven Center for Cancer Biology, VIB
Gianmarco Rinaldi: VIB-KU Leuven Center for Cancer Biology, VIB
Martin F. Orth: Institute of Pathology, Faculty of Medicine, LMU Munich
Ruben Boon: KU Leuven
Axelle Kerstens: KU Leuven
Suet Ying Kwan: University of Texas MD Anderson Cancer Center
Brandon Faubert: UT Southwestern
Andrés Méndez-Lucas: The Francis Crick Institute
Charlotte C. Kopitz: Pharmaceuticals
Ting Chen: Smilow Research Center
Juan Fernandez-Garcia: VIB-KU Leuven Center for Cancer Biology, VIB
João A. G. Duarte: VIB-KU Leuven Center for Cancer Biology, VIB
Arndt A. Schmitz: Pharmaceuticals
Patrick Steigemann: Pharmaceuticals
Mustapha Najimi: Université Catholique de Louvain and Cliniques Universitaires St Luc
Andrea Hägebarth: Pharmaceuticals
Jo A. Ginderachter: Vrije Universiteit Brussel
Etienne Sokal: Université Catholique de Louvain and Cliniques Universitaires St Luc
Naohiro Gotoh: Tokyo University of Marine Science and Technology
Kwok-Kin Wong: Smilow Research Center
Catherine Verfaillie: KU Leuven
Rita Derua: KU Leuven
Sebastian Munck: KU Leuven
Mariia Yuneva: The Francis Crick Institute
Laura Beretta: University of Texas MD Anderson Cancer Center
Ralph J. DeBerardinis: UT Southwestern
Johannes V. Swinnen: Leuven Cancer Institute (LKI)
Leanne Hodson: University of Oxford, Churchill Hospital
David Cassiman: KU Leuven
Chris Verslype: KU Leuven
Sven Christian: Pharmaceuticals
Sylvia Grünewald: Pharmaceuticals
Thomas G. P. Grünewald: Institute of Pathology, Faculty of Medicine, LMU Munich
Sarah-Maria Fendt: VIB-KU Leuven Center for Cancer Biology, VIB

Nature, 2019, vol. 566, issue 7744, 403-406

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-0904-1

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