TY - JOUR
T1 - Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity
AU - Vriens, Kim
AU - Christen, Stefan
AU - Parik, Sweta
AU - Broekaert, Dorien
AU - Yoshinaga, Kazuaki
AU - Talebi, Ali
AU - Dehairs, Jonas
AU - Escalona-Noguero, Carmen
AU - Schmieder, Roberta
AU - Cornfield, Thomas
AU - Charlton, Catriona
AU - Romero-Pérez, Laura
AU - Rossi, Matteo
AU - Rinaldi, Gianmarco
AU - Orth, Martin F.
AU - Boon, Ruben
AU - Kerstens, Axelle
AU - Kwan, Suet Ying
AU - Faubert, Brandon
AU - Méndez-Lucas, Andrés
AU - Kopitz, Charlotte C.
AU - Chen, Ting
AU - Fernandez-Garcia, Juan
AU - Duarte, João A.G.
AU - Schmitz, Arndt A.
AU - Steigemann, Patrick
AU - Najimi, Mustapha
AU - Hägebarth, Andrea
AU - Van Ginderachter, Jo A.
AU - Sokal, Etienne
AU - Gotoh, Naohiro
AU - Wong, Kwok Kin
AU - Verfaillie, Catherine
AU - Derua, Rita
AU - Munck, Sebastian
AU - Yuneva, Mariia
AU - Beretta, Laura
AU - DeBerardinis, Ralph J.
AU - Swinnen, Johannes V.
AU - Hodson, Leanne
AU - Cassiman, David
AU - Verslype, Chris
AU - Christian, Sven
AU - Grünewald, Sylvia
AU - Grünewald, Thomas G.P.
AU - Fendt, Sarah Maria
N1 - Funding Information:
Acknowledgements 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
Funding Information:
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.
Funding Information:
Competing interests A.H., C.C.K., A.S., P.S., S. Christian and S.G. have competing interests as employees of Bayer AG. K.-K.W. is a founder and equity holder of G1 Therapeutics and he has Consulting/Sponsored Research Agreements with AstraZeneca, Janssen, Pfizer, Array, Novartis, Merck, Takeda, Ono, Targimmune and BMS. S.-M.F. has received research funding from Bayer AG and Merck.
PY - 2019/2/21
Y1 - 2019/2/21
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85061803058&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-0904-1
DO - 10.1038/s41586-019-0904-1
M3 - Article
C2 - 30728499
AN - SCOPUS:85061803058
VL - 566
SP - 403
EP - 406
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7744
ER -