title: Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma.
abstract: Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2(-/-)). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2(-/-) mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
authors.forename: Talya L
authors.initials: TL
authors.lastname: Dayton
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
authors.forename: Vasilena
authors.initials: V
authors.lastname: Gocheva
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Miller
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
authors.forename: William J
authors.initials: WJ
authors.lastname: Israelsen
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
authors.forename: Arjun
authors.initials: A
authors.lastname: Bhutkar
authors.affiliation: Metabolite Profiling Platform, Broad Institute, Cambridge, Massachusetts 02142, USA;
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
authors.forename: Alba
authors.initials: A
authors.lastname: Luengo
authors.affiliation: Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, North Grafton, Massachusetts 01536, USA;
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D059305:Diet, High-Fat; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D048788:Growth and Development / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology; D006706:Homeostasis / Q000235:genetics; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D020033:Protein Isoforms; D013963:Thyroid Hormones / Q000235:genetics* / Q000378:metabolism*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins
keywords: HCC; PKM2; metabolism