title: Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis.
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 understood. 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.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA. jlocasal@bidmc.harvard.edu
authors.forename: Jason W
authors.initials: JW
authors.lastname: Locasale
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Grassian
authors.forename: Tamar
authors.initials: T
authors.lastname: Melman
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Mattaini
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.forename: Gregory
authors.initials: G
authors.lastname: Heffron
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
authors.forename: Taru
authors.initials: T
authors.lastname: Muranen
authors.forename: Hadar
authors.initials: H
authors.lastname: Sharfi
authors.forename: Atsuo T
authors.initials: AT
authors.lastname: Sasaki
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Anastasiou
authors.forename: Edouard
authors.initials: E
authors.lastname: Mullarky
authors.forename: Natalie I
authors.initials: NI
authors.lastname: Vokes
authors.forename: Mika
authors.initials: M
authors.lastname: Sasaki
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Gregory
authors.initials: G
authors.lastname: Stephanopoulos
authors.forename: Azra H
authors.initials: AH
authors.lastname: Ligon
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Wagner
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.forename: Joan S
authors.initials: JS
authors.lastname: Brugge
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
mesh_terms: D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050543:Phosphoglycerate Dehydrogenase / Q000378:metabolism*
chemical_list: D050543:Phosphoglycerate Dehydrogenase; D005947:Glucose