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

Roland Nilsson (), Mohit Jain, Nikhil Madhusudhan, Nina Gustafsson Sheppard, Laura Strittmatter, Caroline Kampf, Jenny Huang, Anna Asplund and Vamsi K. Mootha ()
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Roland Nilsson: Unit of Computational Medicine, Karolinska Institutet
Mohit Jain: Broad Institute
Nikhil Madhusudhan: Broad Institute
Nina Gustafsson Sheppard: Unit of Computational Medicine, Karolinska Institutet
Laura Strittmatter: Broad Institute
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

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4128

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