title: Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma.
abstract: BACKGROUND
  While aerobic glycolysis is linked to unconstrained proliferation in cancer, less is known about its physiological role. Why this metabolic program that promotes tumor growth is preserved in the genome has thus been unresolved. We tested the hypothesis that aerobic glycolysis derives from developmental processes that regulate rapid proliferation.
  
  
  METHODS
  We performed an integrated analysis of metabolism and gene expression in cerebellar granule neuron progenitors (CGNPs) with and without Sonic Hedgehog (Shh), their endogenous mitogen. Because our analysis highlighted Hexokinase-2 (Hk2) as a key metabolic regulator induced by Shh, we studied the effect of conditional genetic Hk2 deletion in CGNP development. We then crossed Hk2 conditional knockout mice with transgenic SmoM2 mice that develop spontaneous medulloblastoma and determined changes in SmoM2-driven tumorigenesis.
  
  
  RESULTS
  We show that Shh and phosphoinositide 3-kinase (PI3K) signaling combine to induce an Hk2-dependent glycolytic phenotype in CGNPs. This phenotype is recapitulated in medulloblastoma, a malignant tumor of CGNP origin. Importantly, cre-mediated ablation of Hk2 abrogated aerobic glycolysis, disrupting CGNP development and Smoothened-induced tumorigenesis. Comparing tumorigenesis in medulloblastoma-prone SmoM2 mice with and without functional Hk2, we demonstrate that loss of aerobic glycolysis reduces the aggressiveness of medulloblastoma, causing tumors to grow as indolent lesions and allowing long-term survival of tumor bearing mice.
  
  
  CONCLUSIONS
  Our investigations demonstrate that aerobic glycolysis in cancer derives from developmental mechanisms that persist in tumorigenesis. Moreover, we demonstrate in a primary tumor model the anti-cancer potential of blocking aerobic glycolysis by targeting Hk2.See commentary article:http://www.biomedcentral.com/1741-7007/11/3.
authors.affiliation: Department of Neurology, University of North Carolina, Chapel Hill, NC, 27599, USA. gershont@neurology.unc.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Gershon
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Crowther
authors.forename: Andrey
authors.initials: A
authors.lastname: Tikunov
authors.forename: Idoia
authors.initials: I
authors.lastname: Garcia
authors.forename: Ryan
authors.initials: R
authors.lastname: Annis
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Macdonald
authors.forename: James
authors.initials: J
authors.lastname: Olson
authors.forename: Mohanish
authors.initials: M
authors.lastname: Deshmukh
keywords: Aerobic glycolysis; Brain tumor; Cerebellum; Medulloblastoma; Smoothened; Warburg effect