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Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

Nature Genetics volume 43, pages 869–874 (2011)Cite this article

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Abstract

Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood1,2. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.

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Figure 1: Observation of glycolytic metabolism being diverted into serine and glycine metabolism.
Figure 2: PHGDH amplification in human cancers and requirement for proliferation.
Figure 3: Growth dependence of PHGDH expression and altered serine metabolism in PHGDH-amplified human melanoma cells.
Figure 4: Ectopic expression of PHGDH in breast ductal morphogenesis.

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Acknowledgements

Microscopy data for this study were acquired and analyzed in the Nikon Imaging Center at Harvard Medical School. J.W.L. was supported by postdoctoral fellowships from the US National Institutes of Health (NIH) and the American Cancer Society. A.R.G. is a recipient of a National Science Foundation (NSF) Graduate Research Fellowship. L.C.C. and J.S.B. were supported by grants from the NIH and the National Cancer Institute (NCI). M.G.V.H. was supported by grants from the NIH, NCI, Smith Family, Damon Runyon Cancer Research Foundation and the Burroughs Wellcome Fund. We thank N. Vena for technical assistance with the FISH analysis and K. Webster and I. Carrecedo for help with immunohistochemistry. We thank J. Rabinowitz, A. Carrecedo and S.-C. Ng for helpful comments on the manuscript.

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Authors and Affiliations

  1. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA

    Jason W Locasale, Tamar Melman, Costas A Lyssiotis, Hadar Sharfi, Atsuo T Sasaki, Dimitrios Anastasiou, Edouard Mullarky, Mika Sasaki & Lewis C Cantley

  2. Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

    Jason W Locasale, Tamar Melman, Costas A Lyssiotis, Hadar Sharfi, Atsuo T Sasaki, Dimitrios Anastasiou, Edouard Mullarky, Mika Sasaki, John M Asara & Lewis C Cantley

  3. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, USA

    Alexandra R Grassian, Taru Muranen & Joan S Brugge

  4. Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Katherine R Mattaini, Natalie I Vokes & Matthew G Vander Heiden

  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Adam J Bass, Rameen Beroukhim, Azra H Ligon, Matthew Meyerson, Andrea L Richardson, Lynda Chin & Matthew G Vander Heiden

  6. Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Adam J Bass, Rameen Beroukhim & Matthew Meyerson

  7. Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA

    Gregory Heffron & Gerhard Wagner

  8. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Christian M Metallo & Gregory Stephanopoulos

  9. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Rameen Beroukhim

  10. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Azra H Ligon & Andrea L Richardson

  11. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Matthew Meyerson

  12. Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA

    Lynda Chin

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Contributions

J.W.L., M.G.V.H. and L.C.C. designed the study and wrote the paper. J.W.L., C.A.L., E.M., K.R.M., D.A., H.S., M.G.V.H. and T. Melman carried out experiments. J.W.L. and T. Melman carried out computational analyses. A.J.B., R.B. and M.M. provided help with copy number data. L.C. and A.L.R. provided human cancer samples. N.I.V. and A.H.L. carried out the FISH analysis. J.W.L. and J.M.A. carried out the LC/MS/MS experiments. J.W.L., G.H. and G.W. carried out the NMR experiments. J.W.L., N.I.V., C.M.M. and G.S. carried out the GC/MS experiments. M.S. and A.T.S. generated reagents. J.S.B., T. Muranen and A.R.G. carried out experiments involving acinar morphogenesis and imaging analysis.

Corresponding authors

Correspondence to Jason W Locasale, Lewis C Cantley or Matthew G Vander Heiden.

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Competing interests

J.W.L., M.V.H. and L.C.C. are consultants, scientific advisors and part owners of Agios Pharmaceuticals and hold patents pertaining to targeting cellular metabolism for cancer treatment. Agios Pharmaceuticals is interested in developing therapeutics that target altered metabolism in cancer.

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Locasale, J., Grassian, A., Melman, T. et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43, 869–874 (2011). https://doi.org/10.1038/ng.890

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