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Nature. 2019 Feb 6. doi: 10.1038/s41586-019-0904-1. [Epub ahead of print]

Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity.

Author information

1
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
2
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium.
3
Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
4
Myeloid Cell Immunology Laboratory, VIB Center for Inflammation Research, Brussels, Belgium.
5
Tsukishima Foods Industry, Tokyo, Japan.
6
Cluster of Agricultural Sciences, Faculty of Food and Agricultural Sciences, Fukushima University, Fukushima, Japan.
7
Laboratory of Lipid Metabolism and Cancer, Department of Oncology, Leuven Cancer Institute (LKI), Leuven, Belgium.
8
The Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK.
9
Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
10
Stem Cell Institute, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
11
VIB Bio Imaging Core and VIB-KU Leuven Center for Brain & Disease Research, KU Leuven, Leuven, Belgium.
12
Molecular Neurobiology, Department of Neuroscience, KU Leuven, Leuven, Belgium.
13
Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
14
Children's Medical Center Research Institute, UT Southwestern, Dallas, TX, USA.
15
The Francis Crick Institute, London, UK.
16
Bayer AG, Research & Development, Pharmaceuticals, Berlin, Germany.
17
Perlmutter Cancer Center, NYU Langone Medical Center, Smilow Research Center, New York, NY, USA.
18
Laboratory of Pediatric Hepatology and Cell Therapy, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain and Cliniques Universitaires St Luc, Brussels, Belgium.
19
Department of Food Science and Technology, Tokyo University of Marine Science and Technology, Tokyo, Japan.
20
Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
21
Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX, USA.
22
Department of Hepatology, KU Leuven, Leuven, Belgium.
23
Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
24
Department of Digestive Oncology, KU Leuven, Leuven, Belgium.
25
Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
26
German Cancer Consortium (DKTK), Partner site Munich, Munich, Germany.
27
German Cancer Research Center (DKFZ), Heidelberg, Germany.
28
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium. sarah-maria.fendt@kuleuven.vib.be.
29
Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium. sarah-maria.fendt@kuleuven.vib.be.

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.

PMID:
30728499
DOI:
10.1038/s41586-019-0904-1

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