The intersection between aerobic glycolysis, cerebellar neurogenesis, and medulloblastoma Public Deposited

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  • March 21, 2019
Creator
  • Tech, Katherine
    • Affiliation: School of Medicine, UNC/NCSU Joint Department of Biomedical Engineering
Abstract
  • Aerobic glycolysis supports proliferation in development and cancer through unresolved mechanisms. Aerobic glycolysis, which supports the generation of biomass, is integral to cerebellar granule neuron progenitors (CGNPs) for normal growth and is hijacked in medulloblastoma. Medulloblastoma, the most common malignant pediatric brain tumor, is approached as a disorder of normal brain development. Arising as a disruption of normal cerebellar growth, medulloblastoma exploits the cellular processes used for cerebellar development to promote tumor formation. Thus, genes that are involved in developmentally-regulated progenitor growth may contribute to tumorigenesis when aberrantly expressed. A better understanding of cerebellar development and thus the pathogenesis of medulloblastoma, may lead to more targeted cancer treatments. In response to the developmental mitogen Sonic Hedgehog (SHH), CGNPs increase aerobic glycolysis and up-regulate key glycolytic enzymes Hexokinase-2 (Hk2) and Pyruvate Kinase M2 (Pkm2). HK2, which catalyzes the first step in glycolysis, is required for aerobic glycolysis in brain progenitors and medulloblastomas. Hk2 deletion blocks aerobic glycolysis, disrupts proliferation, and restricts medulloblastoma growth to prolong survival. Moreover, Hk2 was found by others to be up-regulated in medulloblastomas resistant to SHH pathway inhibition by vismodegib treatment. These findings raise the question if Hk2 deletion sensitizes medulloblastoma to vismodegib. Downstream of Hk2, the effect of deleting PKM2 and disrupting the last step in glycolysis in cerebellar neurogenesis and medulloblastoma is unknown. This dissertation examines the importance of aerobic glycolysis to development and cancer. Specifically, I determined the effect of Pkm2 deletion on the cerebellar neurogenesis and medulloblastoma tumorigenesis and the effect of vismodegib treatment on Hk2-deleted medulloblastomas. I demonstrate that CGNPs and medulloblastomas specifically express Pkm as the less active PKM2 isoform. Pkm2 deletion in CGNPs reduces aerobic glycolysis, alters metabolism to increase progenitor proliferation, and accelerates medulloblastoma growth to shorten survival. Thus PKM2 is not required for neural progenitor proliferation or tumorigenesis. Rather, the loss of pyruvate kinase releases cells from growth inhibition. I also found that vismodegib treatment of Hk2-deleted tumors further restricts tumor growth but does not extend survival. Together, these studies demonstrate the potential of targeting aerobic glycolysis as an anti-cancer strategy.
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  • In Copyright
Advisor
  • Tommerdahl, Mark Allen
  • Macdonald, Jeffrey
  • Deshmukh, Mohanish
  • Gershon, Timothy
  • Dennis, Robert G.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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