Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma Public Deposited

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Creator
  • Crowther, Andrew J
    • Affiliation: School of Medicine, Department of Neurology
  • Tikunov, Andrey
    • Affiliation: School of Medicine, UNC/NCSU Joint Department of Biomedical Engineering
  • Olson, James
    • Other Affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
  • Macdonald, Jeffrey
    • Affiliation: School of Medicine, UNC/NCSU Joint Department of Biomedical Engineering
  • Yuan, Hong
    • Affiliation: School of Medicine, Department of Radiology
  • Gershon, Timothy
    • Affiliation: School of Medicine, Neuroscience Center, Department of Neurology, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Garcia, Idoia
    • Affiliation: School of Medicine, Department of Neurology
  • Miller, C. Ryan
    • Affiliation: School of Medicine, Neuroscience Center, Department of Pathology and Laboratory Medicine, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Annis, Ryan
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
  • Deshmukh, Mohanish
    • Affiliation: School of Medicine, Neuroscience Center, N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology
Abstract
  • 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.
Date of publication
Identifier
  • doi:10.1186/2049-3002-1-2
Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Timothy R Gershon et al.; licensee BioMed Central Ltd.
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Journal title
  • Cancer & Metabolism
Journal volume
  • 1
Journal issue
  • 1
Page start
  • 2
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 2049-3002
Bibliographic citation
  • Cancer & Metabolism. 2013 Jan 23;1(1):2
Access
  • Open Access
Publisher
  • BioMed Central Ltd
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