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.
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Data availability
The authors declare that all data supporting the findings of this study are available within the article, its Extended Data, Source Data or from the corresponding author upon reasonable request.
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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 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.
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Nature thanks Andrew Hoy, Almut Schulze and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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Authors and Affiliations
Contributions
In investigation and validation, K.V., S. Christen and S.P. generated knockdown and overexpression cell lines; K.V., S. Christen, S.P., D.B., C.E.-N. and L.R.-P. quantified FADS2 gene expression; K.V., S. Christen and S.P. performed growth and labelling experiments; growth experiments were reproduced independently; K.V. and S. Christen performed reverse labelling experiments; K.V., S. Christen, S.P., D.B. and R.S. performed metabolite extractions; K.V., S. Christen, R.S. and K.Y. performed metabolite measurement; K.V., S.P., G.R. and M.R. analysed FADS2 protein data; T. Cornfield, C.C. and L.H. analysed phospholipid-bound sapienate and palmitoleate; A.T. and J.D. performed phospholipidomic analysis and assessed lipid peroxidation sensitivity; A.K. analysed membrane fluidity; K.V., D.B., R.S. and C.C.K. performed mouse experiments; K.V., M.F.O., B.F., R.J.D., D.C., C. Verslype and T.G.P.G. collected and assessed human clinical samples. T.G.P.G. and M.F.O. performed haematoxylin and eosin staining. In formal analysis, K.V., S. Christen and S.-M.F. interpreted all data, except data from haematoxylin and eosin staining, which were interpreted by T.G.P.G. and M.F.O. The following authors provided resources: M.N. and E.S. provided primary hepatocytes; R.B. and C. Verfaillie advised on genetic engineering and primary hepatocytes; B.F. and R.J.D. provided human lung tissue and plasma samples; D.C., C. Verslype, S. Christian, S.G., A.S. and T.G.P.G. provided human liver tissue and plasma samples; N.G., J.V.S. and L.H. advised on lipid and fatty acid analysis. S.M. advised on membrane fluidity; R.D., J.F.-G. and J.A.G.D. supported the development of the mass spectrometry method; A.M.-L., M.Y., S.Y.K. and L.B. provided liver tissue and plasma from genetic mouse models; and A.S., P.S., A.H., J.A.V.G., S. Christian, S.G., A.S., T. Chen, K.-K.W. provided reagents. S.-M.F. advised on experiments and analysis. This work was conceptualized by K.V., S. Christen and S.-M.F. K.V. provided visualization. S.-M.F. wrote the original draft, which was reviewed and edited by K.V., S. Christen and S.-M.F. S.-M.F. supervised this work, and acquired funding.
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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.
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Extended data figures and tables
Extended Data Fig. 1 SCD-independent cancer cells produce sapienate.
a, Schematic overview of fatty acid metabolism. AcCoA, acetyl-coenzyme A; SCD1/5, stearoyl-CoA desaturase 1 and 5; Elovl5/6, elongation of very long chain fatty acids protein 5 and 6. b–e, SCD desaturation activity based on the palmitoleate-to-palmitate ratio, oleate-to-stearate ratio, and palmitoleate and palmitate synthesis upon treatment with Merck Frosst compound 3j (HUH7 and A549, 2 nM; H460 and DU145, 1 nM; MDA-MB-468 and T47D, 0.5 nM; b–d, n = 3; e, HUH7, n = 3; A459, n = 3; H460, n = 6 (control) and n = 4 (SCD inhibitor); DU145, n = 3; MDA-MB-468, n = 5; T47D, n = 5 (control) and n = 6 (SCD inhibitor)). Unpaired two-sided Student’s t-tests with Holm–Sidak multiple comparisons. f–h, Correlation between SCD independence and palmitate synthesis, growth rate or total fatty acid abundance (n = 3). SCD independence was defined as area under the cell number curve of Fig. 1a. Palmitate synthesis was derived from e. Total fatty acid abundance was derived from Extended Data Fig. 2a. Trend line (dashed line) and 95% confidence intervals (dotted lines) are depicted. Cancer cell experiments were performed in low FBS DMEM (1%, HUH7; 0.5%, others) with a treatment of 72 h. Error bars represent mean ± s.d. from biologically independent samples.
Extended Data Fig. 2 Sapienate is produced via FADS2 in cancer cells.
a, Heat map representing fatty acid abundances with or without treatment with Merck Frosst compound 3j (HUH7 and A549, 2 nM; H460 and DU145, 1 nM; MDA-MB-468 and T47D, 0.5 nM), normalized to the highest abundance of each fatty acid across all cell lines and conditions (Fig. 1b, Supplementary Table 1a). Over 90% reduction, white; no reduction, dark green. b, c, Desaturation activity to sapienate upon treatment with Merck Frosst compound 3j (HUH7 and A549, 2 nM; H460 and DU145, 1 nM; MDA-MB-468 and T47D, 0.5 nM; n = 3). Unpaired two-sided Student’s t-tests with Holm–Sidak multiple comparisons. d, Sapienate-to-palmitate ratio in HUH7 (n = 6) versus freshly isolated primary human hepatocytes (PHH; n = 3), DU145 (n = 6) versus RWPE-1 (n = 6) prostate cells, and MDA-MB-468 (n = 6) and T47D (n = 6) versus MCF10A (n = 6) breast cells. Unpaired Student’s t-tests and Welch’s correction (HUH7 versus PHH and DU145 versus RWEP-1); one-way ANOVA with Dunnett’s multiple comparisons (MDA-MB-468 and T47D versus MCF10A). e, Tumour weight of HUH7 subcutaneous xenografts treated with or without Merck Frosst compound 3j (n = 8, one experiment; 1.5 mg per kg twice daily p.o.). Unpaired Student’s t-test with Welch’s correction. f, g, FADS2 gene expression in cells with or without Merck Frosst compound 3j, as described in b and c, normalized to T47D cells (n = 3). One-way ANOVA with Tukey’s multiple comparisons (f); unpaired Student’s t-tests with Holm–Sidak multiple comparisons (g). h, FADS2 protein expression in the same conditions as in d. Statistics as described in d. n = 3. i, Expression of FADS2 gene or FADS2 protein in HUH7 and A549 cells upon FADS2 silencing, normalized to control (gene, HUH7, n = 3; A549, n = 6; protein, n = 3 (except for A549 shFADS2-2, n = 2)). One-way ANOVA with Dunnett’s multiple comparisons. Cancer cell experiments were performed in low FBS DMEM (1%, HUH7; 0.5%, others) with a treatment of 72 h. Error bars represent s.d. (in vitro) or s.e.m. (in vivo) from mean of biologically independent samples (in vitro) or mice (in vivo).
Extended Data Fig. 3 Sapienate rather than arachidonate metabolism causes SCD independence.
a, Relative FADS2 gene or FADS2 protein expression and desaturation activity to sapienate in MDA-MB-468 control and FADS2 overexpression cells with DMSO or 0.5 nM Merck Frosst compound 3j, normalized to control (n = 3). Unpaired two-sided Student’s t-test. b, Relative FADS2 gene expression in tumour nodules from HUH7 control or FADS2 knockdown orthotopic xenografts with vehicle or Merck Frosst compound 3j (1.5 mg per kg twice daily p.o.; n = 4; one experiment), normalized to control. One-way ANOVA with Tukey’s multiple comparisons. c, d, Relative desaturation activity from palmitate to sapienate or palmitoleate in normal adjacent liver (L) and tumour nodules (T), in the same model as described in f, normalized to normal liver controls. Control + vehicle (L), n = 18 (c) or n = 20 (d); control + vehicle (T), n = 18 (c) or n = 20 (d); control + SCD inhibition (L), n = 14 (c, d); control + SCD inhibition (T), n = 13 (c) or n = 14 (d); shFADS2-2 + vehicle (L), n = 19 (c, d); shFADS2-2 + vehicle (T) n = 18 (c, d); shFADS2-2 + SCD inhibition (L), n = 15 (c) or n = 16 (d); shFADS2-2 + SCD inhibition (T), n = 15 (c, d); two experiments. Two-way ANOVA with Sidak’s multiple comparisons. e, f, Desaturation activity from linoleate to γ-linolenate, on the basis of the γ-linolenate-to-linoleate ratio and arachidonate abundance in HUH7 and A549 control (non-targeting shRNA) and FADS2 knockdown (using one of two FADS2 shRNAs) cells (n = 3). One-way ANOVA with Dunnett’s multiple comparisons. g, h, Linoleate and arachidonate abundance in normal adjacent mouse liver and tumour nodules from HUH7 control (non-targeting shRNA) or FADS2 knockdown (shFADS2-2) orthotopic xenografts treated with vehicle or Merck Frosst compound 3j (1.5 mg per kg twice daily p.o.). Control + vehicle (L), n = 12 (g) or n = 14 (h); control + vehicle (T), n = 13 (g) or n = 14 (h); control + SCD inhibition (L), n = 14 (g) or n = 15 (h); control + SCD inhibition (T) n = 14 (g) or n = 16 (h); shFADS2-2 + vehicle (L), n = 14 (g) or n = 16 (h); shFADS2-2 + vehicle (T), n = 13 (g) or n = 15 (h); shFADS2-2 + SCD inhibition (L), n = 15 (g) or n = 18 (h); shFADS2-2 + SCD inhibition (T), n = 15 (g) or n = 16 (h); two experiments. Two-way ANOVA with Tukey’s multiple comparisons. Cancer cell experiments were performed in low FBS DMEM (1%, HUH7; 0.5%, others) with a treatment of 72 h. Error bars represent s.d. (in vitro) or s.e.m. (in vivo) from mean of biologically independent samples (in vitro) or mice (in vivo).
Extended Data Fig. 4 Carbons from sapienate are detected in octadecenoate.
a–f, 13C enrichment of palmitate or stearate from 13C6-glucose in HUH7 or A549 cells in control conditions (ethanol, black) or upon 12C-sapienate supplementation (blue). Cells were grown in 10% dialysed FBS DMEM containing 4.5 g per l 13C6 glucose for 1 week, after which cells were grown for 72 h in 0.5% FBS DMEM containing 4.5 g per l 13C6 glucose supplemented with ethanol or 20 μM 12C-sapienate. The purpose of this experiment was to trace the incorporation of carbons from sapienate into cis-8-octadecenoate. Palmitate and stearate were measured as controls. Because 13C-labelled sapienate is not commercially available, we performed a reverse labelling in which we pre-labelled HUH7 and A549 cells with 13C6-glucose to enrich cis-8-octadecenoate with 13C. Then, we supplemented these cells with unlabelled sapienate in the presence of 13C6-glucose and determined the 13C enrichment of octadecenoate. If sapienate is elongated to cis-8-octadecenoate, we expect a shift in the 13C enrichment from higher to lower octadecenoate isotopologues. We found that supplementation of unlabelled sapienate shifted the 13C enrichment accordingly (a, d). Moreover, the largest 13C enrichment increase was found in the M + 2 isotopologue, which indicates the elongation of unlabelled sapienate to octadecenoate with 13C-labelled acetyl-CoA. As expected, sapienate supplementation did not change (or only marginally changed) the 13C enrichment of palmitate and stearate (b, c, e, f). Unpaired two-sided Student’s t-tests; n = 3. Error bars represent mean ± s.d. from biologically independent samples.
Extended Data Fig. 5 Sapienate is elongated to cis-8-octadecenoate.
a, Relative cis-8-octadecenoate abundance in cancer cells, normalized to T47D cells. HUH7, n = 3; A549, n = 3; H460, n = 5; DU145, n = 3; MDA-MB-468, n = 5; T47D, n = 5. One-way ANOVA with Tukey’s multiple comparisons. b, c, Relative cis-8-octadecenoate abundances in HUH7 and A549 control (non-targeting shRNA) and FADS2 knockdown (one of two FADS2 shRNAs) cells in control condition (ethanol) or upon supplementation with 20 μM sapienate, normalized to control. HUH7, control, n = 6 (ethanol) or n = 3 (sapienate); shFADS2-1, n = 3; shFADS2-2, n = 6 (ethanol) or n = 3 (sapienate); A549, control, n = 6; shFADS2-1, n = 3; shFADS2-2, n = 3. Data values are shown in Supplementary Table 1c, d. Two-way ANOVA with Tukey’s multiple comparisons. d, Relative proliferation of MDA-MB-468 cells with ethanol (n = 9) or 20 μM cis-8-octadecenoate (n = 3) upon treatment with DMSO or 0.5 nM Merck Frosst compound 3j. Data are normalized to control, with error bars representing s.e.m. Two-way ANOVA with Tukey’s multiple comparisons. e, f, Relative proliferation of HUH7 and A549 control (non-targeting shRNA) and knockdown (shFADS2) cells with ethanol or 20 μM cis-8-octadecenoate upon treatment with DMSO or 2 nM Merck Frosst compound 3j. HUH7, control, n = 9; shFADS2-1, n = 6; shFADS2-2, n = 9; A549: EtOH, n = 6; cis-8-C18:1, n = 3. Data are normalized to control. Two-way ANOVA with Tukey’s multiple comparisons. Only statistics for pairwise comparisons are depicted. Cancer cell experiments were performed in low FBS DMEM (1%, HUH7; 0.5%, all other cancer cells) with a treatment of 72 h. Error bars represent mean ± s.d. from biologically independent samples, unless otherwise noted.
Extended Data Fig. 6 Sapienate and cis-8-octadecenoate are used in membranes.
a–d, Heat map representing abundance changes of phosphatidylcholine (a), phosphatidylethanolamine (b), phosphatidylserine (c) and phosphatidylinositol (d) species in control and FADS2 knockdown HUH7 and A549 cells, relative to control. HUH7, control, n = 3; shFADS2-1, n = 4; shFADS2-2, n = 5; A549, n = 5. Only significant differences are depicted as fold change (log2(change with shRNA versus control)). X, blank or excluded values. Phospholipid species carrying sapienate or palmitoleate are depicted in bold red, and are listed in Supplementary Table 1e. Two-way ANOVA with Dunnett’s multiple comparisons. e, Relative distribution of phospholipid species in HUH7 (n = 2) and A549 (n = 5) cells with non-targeting shRNA (control). f, Membrane fluidity based on the ordered-to-disordered lipid ratio in HUH7 and A549 with a non-targeting shRNA (control, black) or one of two different shRNAs targeting FADS2 (brown (shFADS2-1) and orange (shFADS2-2)), normalized to control (n = 4). The higher the ordered-to-disordered ratio, the more saturated lipids are present in the membrane. One-way ANOVA with Dunnett’s multiple comparisons. g, Lipid peroxidation sensitivity via MDA assay in HUH7 with a non-targeting shRNA (control; black) or one of two different shRNAs targeting FADS2 (brown (shFADS2-1) and orange (shFADS2-2)) normalized to control (n = 3). Cells were treated with vehicle or 5 μM RSL3, which inhibits glutathione peroxidase 4 and induces lipid peroxidation. Two-way ANOVA with Sidak’s multiple comparisons. Cancer cell experiments were performed in low FBS DMEM (1%, HUH7; 0.5%, all other cancer cells) with a treatment of 72 h. Data are presented as mean ± s.d. from biologically independent samples.
Extended Data Fig. 7 SCD independence and sapienate metabolism occur in medium with glucose and amino acid concentrations that are similar to physiological conditions.
a, Fatty acid concentrations of fetal bovine serum (FBS; n = 4). Low FBS conditions (0.5–1% FBS) correspond to a total fatty acid concentration of 4.31–8.62 μM. b, Sensitivity profile of cancer cells to Merck Frosst compound 3j (white; HUH7 and A549 2 nM; H460 and DU145, 1 nM; MDA-MB-468 and T47D, 0.5 nM) in BLM12,13, normalized to control. HUH7, n = 3; A549, n = 3; H460, n = 6; DU145, n = 6, MDA-MB-468, n = 3; T47D, n = 9. Two-way ANOVA with Dunnett’s multiple comparisons. c, d, Sensitivity profile of HUH7 and A549 control (non-targeting shRNA, black) and knockdown (shFADS2, (brown (shFADS2-1) and orange (shFADS2-2)) cells treated with DMSO (dark bars) or 2 nM Merck Frosst compound 3j (light bars) in BLM12,13, normalized to control (n = 3). Two-way ANOVA with Holm–Sidak multiple comparisons. e, Sensitivity profile of MDA-MB-468 control (black) and FADS2 overexpression (green) cells treated with DMSO (dark bars) or 0.5 nM Merck Frosst compound 3j (light bars) in BLM12,13, normalized to control (n = 3). Two-way ANOVA with Holm–Sidak multiple comparisons. f, Desaturation activity to sapienate based on the sapienate-to-palmitate ratio in cancer cells, in conditions as described in b. n = 3. Unpaired two-sided Student’s t-tests with Holm–Sidak multiple comparisons. g, h, Desaturation activity from palmitate to sapienate based on the sapienate-to-palmitate ratio, in the same conditions as described in c–f. n = 3. One-way ANOVA with Dunnett’s multiple comparisons (g); unpaired Student’s t-test (h). Cancer cell experiments were performed in low FBS BLM (1%, HUH7; 0.5%, all other cancer cells) with a treatment of 72 h. Data are presented as mean ± s.d. from biologically independent samples.
Extended Data Fig. 8 Separation and detection of sapienate and cis-8-octadecenoate.
a, Separation and detection of sapienate (cis-6-hexadecenoate) and palmitoleate (cis-9-hexadecenoate) via GC–MS. Separation was optimized using a standard mix, containing pentadecanoate, sapienate, palmitoleate, palmitate, cis-8-octadecenoate, oleate, vaccinate, linoleate and stearate (top), and the method was subsequently validated by measurement of these fatty acids in biological samples. Bottom, a representative biological sample. b, Separation and detection of cis-8-octadecenoate, oleate (cis-9-octadecenoate) and vaccinate (cis-11-octadecenoate) via GC–FID. Separation was optimized using a standard mix containing cis-8-, cis-9- and cis-11-octadecenoate (top), and the method was subsequently validated by measurement of these fatty acids in biological samples. Bottom, a representative biological sample.
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Vriens, K., Christen, S., Parik, S. et al. Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity. Nature 566, 403–406 (2019). https://doi.org/10.1038/s41586-019-0904-1
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DOI: https://doi.org/10.1038/s41586-019-0904-1
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