title: PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells.
abstract: The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in a Brca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.
authors.affiliation: Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Israelsen
authors.forename: Talya L
authors.initials: TL
authors.lastname: Dayton
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.forename: Brian P
authors.initials: BP
authors.lastname: Fiske
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Hosios
authors.forename: Gary
authors.initials: G
authors.lastname: Bellinger
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Yimin
authors.initials: Y
authors.lastname: Yu
authors.forename: Mika
authors.initials: M
authors.lastname: Sasaki
authors.forename: James W
authors.initials: JW
authors.lastname: Horner
authors.forename: Laura N
authors.initials: LN
authors.lastname: Burga
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xie
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Richard G
authors.initials: RG
authors.lastname: Kibbey
authors.forename: Gerburg M
authors.initials: GM
authors.lastname: Wulf
authors.forename: Dolores
authors.initials: D
authors.lastname: Di Vizio
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005091:Exons; D005260:Female; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D064593:Heterografts; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism*; D012326:RNA Splicing
chemical_list: D007527:Isoenzymes; D011770:Pyruvate Kinase