title: Adaptations of energy metabolism during cerebellar neurogenesis are co-opted in medulloblastoma.
abstract: Recent studies show that metabolic patterns typical of cancer cells, including aerobic glycolysis and increased lipogenesis, are not unique to malignancy, but rather originate in physiologic development. In the postnatal brain, where sufficient oxygen for energy metabolism is scrupulously maintained, neural progenitors nevertheless metabolize glucose to lactate and prioritize lipid synthesis over fatty acid oxidation. Medulloblastoma, a cancer of neural progenitors that is the most common malignant brain tumor in children, recapitulates the metabolic phenotype of brain progenitor cells. During the physiologic proliferation of neural progenitors, metabolic enzymes generally associated with malignancy, including Hexokinase 2 (Hk2) and Pyruvate kinase M2 (PkM2) configure energy metabolism to support growth. In these non-malignant cells, expression of Hk2 and PkM2 is driven by transcriptional regulators that are typically identified as oncogenes, including N-myc. Importantly, N-myc continues to drive Hk2 and PkM2 in medulloblastoma. Similarly E2F transcription factors and PPARγ function in both progenitors and medulloblastoma to optimize energy metabolism to support proliferation. These findings show that the "metabolic transformation" that is a hallmark of cancer is not specifically limited to cancer. Rather, metabolic transformation represents a co-opting of developmental programs integral to physiologic growth. Despite their physiologic origins, the molecular mechanisms that mediate metabolic transformation may nevertheless present ideal targets for novel anti-tumor therapy.
authors.affiliation: Joint Department of Biomedical Engineering, NC State University and UNC Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Tech
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: Mohanish
authors.initials: M
authors.lastname: Deshmukh
authors.affiliation: Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Electronic address: gershont@neurology.unc.edu.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Gershon
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002528:Cerebellar Neoplasms / Q000378:metabolism* / Q000473:pathology; D054022:Cerebrum / Q000502:physiology; D050684:E2F Transcription Factors / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D006019:Glycolysis / Q000502:physiology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology; D008055:Lipids / Q000096:biosynthesis; D050155:Lipogenesis / Q000502:physiology; D008527:Medulloblastoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D055495:Neurogenesis / Q000502:physiology; D047495:PPAR gamma / Q000378:metabolism; D011770:Pyruvate Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*
chemical_list: D050684:E2F Transcription Factors; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; C099927:NMI protein, human; D047495:PPAR gamma; C509239:SHH protein, human; D006593:Hexokinase; D011770:Pyruvate Kinase
keywords: Aerobic glycolysis; Cerebellar development; Hexokinase 2; Medulloblastoma; PkM2; Postnatal neurogenesis