• A Corrigendum to this article was published on 02 August 2017


The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis2,3,4, many others rely on exogenous serine for optimal growth5,6,7. Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models7,8. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

  • Subscribe to Nature for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572–583 (2013)

  2. 2.

    & Genetic selection for enhanced serine metabolism in cancer development. Cell Cycle 10, 3812–3813 (2011)

  3. 3.

    et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476, 346–350 (2011)

  4. 4.

    Enzymes of serine metabolism in normal and neoplastic rat tissues. Biochim. Biophys. Acta 843, 276–281 (1985)

  5. 5.

    et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012)

  6. 6.

    , , , & Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells. Cell Reports 7, 1248–1258 (2014)

  7. 7.

    et al. Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells. Nature 493, 542–546 (2013)

  8. 8.

    et al. Serine deprivation enhances antineoplastic activity of biguanides. Cancer Res. 74, 7521–7533 (2014)

  9. 9.

    et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985)

  10. 10.

    , & N-ethyl-N-nitrosourea treatment of multiple intestinal neoplasia (Min) mice: age-related effects on the formation of intestinal adenomas, cystic crypts, and epidermoid cysts. Cancer Res. 55, 4479–4485 (1995)

  11. 11.

    et al. Serine is a natural ligand and allosteric activator of pyruvate kinase M2. Nature 491, 458–462 (2012)

  12. 12.

    et al. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc. Natl Acad. Sci. USA 109, 6904–6909 (2012)

  13. 13.

    et al. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell 23, 143–158 (2013)

  14. 14.

    , , , & Repositioning metformin for cancer prevention and treatment. Trends Endocrinol. Metab. 24, 469–480 (2013)

  15. 15.

    et al. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Exp. Ther. 302, 510–515 (2002)

  16. 16.

    , & Dose translation from animal to human studies revisited. FASEB J. 22, 659–661 (2008)

  17. 17.

    et al. Metformin pharmacokinetics in mouse tumors: implications for human therapy. Cell Metab. 23, 567–568 (2016)

  18. 18.

    et al. Are metformin doses used in murine cancer models clinically relevant? Cell Metab. 23, 569–570 (2016)

  19. 19.

    , & Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients. Diabetes Res. Clin. Pract. 93, 56–62 (2011)

  20. 20.

    et al. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clin. Nutr. 32, 179–185 (2013)

  21. 21.

    et al. Metformin reduces intracellular reactive oxygen species levels by upregulating expression of the antioxidant thioredoxin via the AMPK–FOXO3 pathway. Biochem. Biophys. Res. Commun. 396, 199–205 (2010)

  22. 22.

    et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife 3, e02242 (2014)

  23. 23.

    , & Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J. 28, 3015–3026 (2009)

  24. 24.

    et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006)

  25. 25.

    et al. Opposing effects of TIGAR- and RAC1-derived ROS on Wnt-driven proliferation in the mouse intestine. Genes Dev. 30, 52–63 (2016)

  26. 26.

    , & Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc. Natl Acad. Sci. USA 109, 20491–20496 (2012)

  27. 27.

    et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005)

  28. 28.

    et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl Acad. Sci. USA 107, 246–251 (2010)

  29. 29.

    et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013)

  30. 30.

    et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012)

  31. 31.

    et al. Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. Nature 497, 633–637 (2013)

  32. 32.

    et al. Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res. 75, 544–553 (2015)

  33. 33.

    et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011)

  34. 34.

    et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat. Genet. 47, 1475–1481 (2015)

  35. 35.

    et al. LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539, 390–395 (2016)

  36. 36.

    et al. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353, 1161–1165 (2016)

  37. 37.

    et al. Application of holistic liquid chromatography-high resolution mass spectrometry based urinary metabolomics for prostate cancer detection and biomarker discovery. PLoS One 8, e65880 (2013)

  38. 38.

    , & Comparative utilization of a crystalline amino-acid diet and a methionine-fortified casein diet by young-rats and mice. Nutr. Res. 4, 891–895 (1984)

  39. 39.

    , & A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 247, 322–324 (1990)

  40. 40.

    et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 256, 668–670 (1992)

  41. 41.

    et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009)

  42. 42.

    et al. Tissue-specific and inducible Cre-mediated recombination in the gut epithelium. Genesis 39, 186–193 (2004)

  43. 43.

    , , & Serine metabolism supports the methionine cycle and DNA/RNA methylation through de novo ATP synthesis in cancer cells. Mol. Cell 61, 210–221 (2016)

  44. 44.

    et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 2, 345–357 (2017)

Download references


We thank the BSU facilities at the CRUK Beatson Institute, C. Nixon, the histology facility and A. Hock for technical assistance, G. Kalna and R. Daly for advice on statistics and C. Winchester for reading the manuscript. We also thank R. DePinho for the Kras-inducible pancreatic cell lines. This work was funded by Cancer Research UK Grant C596/A10419, ERC Grant 322842-METABOp53 and a CRUK Career Development Fellowship (O.D.K.M.) C53309/A19702. O.S. and D.F.V. are funded by CRUK and an ERC Starting Grant (311301).

Author information

Author notes

    • Pearl Lee
    • , Fatih Ceteci
    •  & Karen H. Vousden

    Present addresses: Abrahamson Family Cancer Research Institute, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104, USA (P.L.); Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany (F.C.); The Crick Institute, 1 Midland Road, London NW1 1AT, UK (K.H.V.).


  1. Cancer Research UK Beatson Institute, Switchback Road, Glasgow G61 1BD, UK

    • Oliver D. K. Maddocks
    • , Dimitris Athineos
    • , Eric C. Cheung
    • , Pearl Lee
    • , Niels J. F. van den Broek
    • , Gillian M. Mackay
    • , Christiaan F. Labuschagne
    • , David Gay
    • , Flore Kruiswijk
    • , Julianna Blagih
    • , David F. Vincent
    • , Kirsteen J. Campbell
    • , Fatih Ceteci
    • , Owen J. Sansom
    • , Karen Blyth
    •  & Karen H. Vousden
  2. University of Glasgow Institute of Cancer Sciences, Switchback Road, Glasgow G61 1QH, UK

    • Oliver D. K. Maddocks
    • , Tong Zhang
    •  & Owen J. Sansom


  1. Search for Oliver D. K. Maddocks in:

  2. Search for Dimitris Athineos in:

  3. Search for Eric C. Cheung in:

  4. Search for Pearl Lee in:

  5. Search for Tong Zhang in:

  6. Search for Niels J. F. van den Broek in:

  7. Search for Gillian M. Mackay in:

  8. Search for Christiaan F. Labuschagne in:

  9. Search for David Gay in:

  10. Search for Flore Kruiswijk in:

  11. Search for Julianna Blagih in:

  12. Search for David F. Vincent in:

  13. Search for Kirsteen J. Campbell in:

  14. Search for Fatih Ceteci in:

  15. Search for Owen J. Sansom in:

  16. Search for Karen Blyth in:

  17. Search for Karen H. Vousden in:


O.D.K.M. and K.H.V. conceived and designed the study. D.A., K.B., E.C.C., D.G., J.B., D.F.V. and O.J.S. performed/supervised GEMM/xenograft/allograft studies; D.A., K.B., O.D.K.M. and E.C.C. performed GEMM/xenograft/allograft data analysis. K.J.C. supplied cell lines and advised on allograft experiments. LC–MS was conducted by N.J.F.v.d.B., G.M.M., C.F.L. and T.Z. Metabolomics sample preparation and data analysis was performed by O.D.K.M. and T.Z. F.C. derived and cultured organoids; P.L. and E.C.C. cultured and analysed organoids; P.L. and O.D.K.M. cultured and analysed other cell lines. F.K. cultured cells and performed macropinocytosis assays and data analysis. The manuscript was written by O.D.K.M. and K.H.V.

Competing interests

K.H.V. is on the Science Advisory Board of Raze Therapeutics. O.D.K.M. and K.H.V. contributed to CRUK Cancer Research Technology filing of UK Patent Application no. 1609441.9.

Corresponding authors

Correspondence to Oliver D. K. Maddocks or Karen H. Vousden.

Reviewer Information Nature thanks I. Topisirovic and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figure 1

    This file contains the uncropped blots.

About this article

Publication history






Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.