Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis

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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.

Author information

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.

Correspondence to Jason W Locasale or 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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