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Cycling back to folate metabolism in cancer

Nature Cancer (2024)Cite this article

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Abstract

Metabolic changes contribute to cancer initiation and progression through effects on cancer cells, the tumor microenvironment and whole-body metabolism. Alterations in serine metabolism and the control of one-carbon cycles have emerged as critical for the development of many tumor types. In this Review, we focus on the mitochondrial folate cycle. We discuss recent evidence that, in addition to supporting nucleotide synthesis, mitochondrial folate metabolism also contributes to metastasis through support of antioxidant defense, mitochondrial protein synthesis and the overflow of excess formate. These observations offer potential therapeutic opportunities, including the modulation of formate metabolism through dietary interventions and the use of circulating folate cycle metabolites as biomarkers for cancer detection.

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Fig. 1: The SSP, the folate cycle and the methionine cycle.
Fig. 2: Folate metabolism in the cytoplasm and mitochondria.
Fig. 3: Mitochondrial and cytosolic NADPH use in cancer cells and hepatocytes.
Fig. 4: Inputs and outputs of formate metabolism.
Fig. 5: Potential consequences of formate metabolism in cancer.

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Acknowledgements

The work was funded by Cancer Research UK grant C596/A26855 and ERC-2020-ADG PancObese 101020641 and supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CC2073), the UK Medical Research Council (CC2073) and the Wellcome Trust (CC2073).

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  1. Marc Hennequart

    Present address: Namur Research Institute for Life Sciences (NARILIS), Molecular Physiology Unit (URPHYM), University of Namur, Namur, Belgium

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    Younghwan Lee, Karen H. Vousden & Marc Hennequart

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K.H.V. is on the board of directors, is a shareholder of Bristol Myers Squibb and is on the science advisory board (with stock options) of PMV Pharma, Raze Therapeutics, Volastra Pharmaceuticals and Kovina Therapeutics. She is on the SAB of Ludwig Cancer and is a cofounder and consultant (with stock options) of Faeth Therapeutics. She has received research funding from Astex Pharmaceuticals and AstraZeneca and has contributed to CRUK Cancer Research Technology filing patent application WO/2017/144877. The other authors declare no conflicts of interest.

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Lee, Y., Vousden, K.H. & Hennequart, M. Cycling back to folate metabolism in cancer. Nat Cancer (2024). https://doi.org/10.1038/s43018-024-00739-8

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