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      headline:Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis
      description:Jason Locasale, Lewis Cantley, Matthew Vander Heiden and colleagues show that PHGDH is amplified in some human cancers and diverts a relatively large amount of glycolytic carbon into serine and glycine biosynthesis. They further show that PHGDH-amplified cancer cells become dependent on PHGDH for their growth, suggesting that the altered metabolic flux driven by this amplification contributes to oncogenesis. 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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      dateModified:2011-07-31T00:00:00Z
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         Energy metabolism
         Oncogenesis
         Biomedicine
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         Cancer Research
         Agriculture
         Gene Function
         Animal Genetics and Genomics
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      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
      name:Cancer Program, Broad Institute of MIT and Harvard, Cambridge, USA
      name:Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
      name:Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
      name:Department of Pathology, Brigham and Women's Hospital, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
      name:Cancer Program, Broad Institute of MIT and Harvard, Cambridge, USA
      name:Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
      name:Department of Pathology, Brigham and Women's Hospital, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
      name:Department of Dermatology, Harvard Medical School, Boston, USA
      name:Department of Biochemistry and Molecular Pharmacology, Harvard Medical School, Boston, USA
      name:Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, USA
      name:Department of Cell Biology, Harvard Medical School, Boston, USA
      name:Department of Systems Biology, Harvard Medical School, Boston, USA
      name:Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, USA
      name:Department of Biology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
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