Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer.
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.
1] Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden [2] Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden [3].
Roland
R
Nilsson
1] Broad Institute, Cambridge, Massachusetts 02142, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Molecular Biology and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [4] Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [5] [6].
Mohit
M
Jain
1] Broad Institute, Cambridge, Massachusetts 02142, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Molecular Biology and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Nikhil
N
Madhusudhan
1] Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, 17176 Stockholm, Sweden [2] Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden.
Nina Gustafsson
NG
Sheppard
1] Broad Institute, Cambridge, Massachusetts 02142, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Molecular Biology and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Laura
L
Strittmatter
Department of Immunology, Genetics & Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden.
Caroline
C
Kampf
La Jolla Institute for Allergy and Immunology, San Diego, California 92037, USA.
Jenny
J
Huang
Department of Immunology, Genetics & Pathology, Science for Life Laboratory, Uppsala University, 75185 Uppsala, Sweden.
Anna
A
Asplund
1] Broad Institute, Cambridge, Massachusetts 02142, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Molecular Biology and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Vamsi K
VK
Mootha
D000619:Aminohydrolases / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D005492:Folic Acid / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics*; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D009097:Multienzyme Complexes; D012333:RNA, Messenger; C055342:methylene tetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases