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

Abstract

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.

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Acknowledgements

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.).

Affiliations

  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

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Contributions

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.

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https://doi.org/10.1038/nature22056

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