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The ins and outs of serine and glycine metabolism in cancer

Nature Metabolism volume 3, pages 131–141 (2021)Cite this article

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Abstract

Cancer cells reprogramme their metabolism to support unrestrained proliferation and survival in nutrient-poor conditions. Whereas non-transformed cells often have lower demands for serine and glycine, several cancer subtypes hyperactivate intracellular serine and glycine synthesis and become addicted to de novo production. Copy-number amplifications of serine- and glycine-synthesis genes and genetic alterations in common oncogenes and tumour-suppressor genes enhance serine and glycine synthesis, resulting in high production and secretion of these oncogenesis-supportive metabolites. In this Review, we discuss the contribution of serine and glycine synthesis to cancer progression. By relying on de novo synthesis pathways, cancer cells are able to enhance macromolecule synthesis, neutralize high levels of oxidative stress and regulate methylation and tRNA formylation. Furthermore, we discuss the immunosuppressive potential of serine and glycine, and the essentiality of both amino acids to promoting survival of non-transformed neighbouring cells. Finally, we point to the emerging data proposing moonlighting functions of serine- and glycine-synthesis enzymes and examine promising small molecules targeting serine and glycine synthesis.

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Fig. 1: The anabolic serine and glycine synthesis side-branch of glycolysis.
Fig. 2: Amplifications of serine- and glycine-synthesis genes occur in many cancer types.
Fig. 3: Outputs of serine and glycine synthesis and one-carbon metabolism.
Fig. 4: Regulators of serine and glycine synthesis.
Fig. 5: Serine and glycine synthesis in the microenvironment.

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Acknowledgements

S.L.G. received a SB PhD fellowship from Fonds Wetenschappelijk Onderzoek (FWO) (1S14517N). E.H. is a FWO PhD fellow fundamental research (1106121N). K.D.K. was supported by a grant from Stichting Tegen Kanker (2016-112) and funding from the KU Leuven Research Council (C1 grant C14/18/104). K.R.K. was funded by the Emmanuel van der Schueren postdoctoral fellowship from Kom op tegen Kanker and a research grant from FWO (FWO KAN2018 1501419N).

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Author notes

  1. These authors contributed equally: Shauni L. Geeraerts, Elien Heylen.

  2. These authors jointly supervised this work: Kim De Keersmaecker, Kim R. Kampen.

Authors and Affiliations

  1. Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Leuven, Belgium

    Shauni L. Geeraerts, Elien Heylen, Kim De Keersmaecker & Kim R. Kampen

  2. Maastricht University Medical Centre, Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands

    Kim R. Kampen

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  1. Shauni L. Geeraerts
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  4. Kim R. Kampen
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Contributions

S.L.G., E.H., K.D.K. and K.R.K. wrote the review. S.L.G., E.H. and K.R.K. made the figures and tables. K.D.K. and K.R.K. supervised the entire study. All authors have participated in the manuscript review and approved the final manuscript.

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Correspondence to Kim De Keersmaecker or Kim R. Kampen.

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Peer review information Primary Handling Editor: George Caputa. Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work.

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Geeraerts, S.L., Heylen, E., De Keersmaecker, K. et al. The ins and outs of serine and glycine metabolism in cancer. Nat Metab 3, 131–141 (2021). https://doi.org/10.1038/s42255-020-00329-9

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