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Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer

Author

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  • Roland Nilsson

    (Unit of Computational Medicine, Karolinska Institutet
    Center for Molecular Medicine, Karolinska Institutet)

  • Mohit Jain

    (Broad Institute
    Harvard Medical School
    Massachusetts General Hospital
    Brigham and Women's Hospital)

  • Nikhil Madhusudhan

    (Broad Institute
    Harvard Medical School
    Massachusetts General Hospital)

  • Nina Gustafsson Sheppard

    (Unit of Computational Medicine, Karolinska Institutet
    Center for Molecular Medicine, Karolinska Institutet)

  • Laura Strittmatter

    (Broad Institute
    Harvard Medical School
    Massachusetts General Hospital)

  • Caroline Kampf

    (Genetics & Pathology, Science for Life Laboratory, Uppsala University)

  • Jenny Huang

    (La Jolla Institute for Allergy and Immunology)

  • Anna Asplund

    (Genetics & Pathology, Science for Life Laboratory, Uppsala University)

  • Vamsi K. Mootha

    (Broad Institute
    Harvard Medical School
    Massachusetts General Hospital)

Abstract

Metabolic remodeling is now widely regarded as a hallmark of cancer, but it is not clear whether individual metabolic strategies are frequently exploited by many tumours. Here we compare messenger RNA profiles of 1,454 metabolic enzymes across 1,981 tumours spanning 19 cancer types to identify enzymes that are consistently differentially expressed. Our meta-analysis recovers established targets of some of the most widely used chemotherapeutics, including dihydrofolate reductase, thymidylate synthase and ribonucleotide reductase, while also spotlighting new enzymes, such as the mitochondrial proline biosynthetic enzyme PYCR1. The highest scoring pathway is mitochondrial one-carbon metabolism and is centred on MTHFD2. MTHFD2 RNA and protein are markedly elevated in many cancers and correlated with poor survival in breast cancer. MTHFD2 is expressed in the developing embryo, but is absent in most healthy adult tissues, even those that are proliferating. Our study highlights the importance of mitochondrial compartmentalization of one-carbon metabolism in cancer and raises important therapeutic hypotheses.

Suggested Citation

  • Roland Nilsson & Mohit Jain & Nikhil Madhusudhan & Nina Gustafsson Sheppard & Laura Strittmatter & Caroline Kampf & Jenny Huang & Anna Asplund & Vamsi K. Mootha, 2014. "Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4128
    DOI: 10.1038/ncomms4128
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    Cited by:

    1. Martha M. Zarou & Kevin M. Rattigan & Daniele Sarnello & Engy Shokry & Amy Dawson & Angela Ianniciello & Karen Dunn & Mhairi Copland & David Sumpton & Alexei Vazquez & G. Vignir Helgason, 2024. "Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. André Schultz & Amina A Qutub, 2016. "Reconstruction of Tissue-Specific Metabolic Networks Using CORDA," PLOS Computational Biology, Public Library of Science, vol. 12(3), pages 1-33, March.
    3. Natalia Pardo-Lorente & Anestis Gkanogiannis & Luca Cozzuto & Antoni Gañez Zapater & Lorena Espinar & Ritobrata Ghose & Jacqueline Severino & Laura García-López & Rabia Gül Aydin & Laura Martin & Mari, 2024. "Nuclear localization of MTHFD2 is required for correct mitosis progression," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    4. Camilla Tombari & Alessandro Zannini & Rebecca Bertolio & Silvia Pedretti & Matteo Audano & Luca Triboli & Valeria Cancila & Davide Vacca & Manuel Caputo & Sara Donzelli & Ilenia Segatto & Simone Vodr, 2023. "Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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