title: Spinal Myxopapillary Ependymomas Demonstrate a Warburg Phenotype.
abstract: OBJECTIVE
  Myxopapillary ependymoma (MPE) is a distinct histologic variant of ependymoma arising commonly in the spinal cord. Despite an overall favorable prognosis, distant metastases, subarachnoid dissemination, and late recurrences have been reported. Currently, the only effective treatment for MPE is gross-total resection. We characterized the genomic and transcriptional landscape of spinal ependymomas in an effort to delineate the genetic basis of this disease and identify new leads for therapy.
  
  
  METHODS
  Gene expression profiling was performed on 35 spinal ependymomas, and copy number profiling was done on an overlapping cohort of 46 spinal ependymomas. Functional validation experiments were performed on tumor lysates consisting of assays measuring pyruvate kinase M activity (PKM), hexokinase activity (HK), and lactate production.
  
  
  RESULTS
  At a gene expression level, we demonstrate that spinal grade II and MPE are molecularly and biologically distinct. These are supported by specific copy number alterations occurring in each histologic variant. Pathway analysis revealed that MPE are characterized by increased cellular metabolism, associated with upregulation of HIF1α. These findings were validated by Western blot analysis demonstrating increased protein expression of HIF1α, HK2, PDK1, and phosphorylation of PDHE1A. Functional assays were performed on MPE lysates, which demonstrated decreased PKM activity, increased HK activity, and elevated lactate production.
  
  
  CONCLUSIONS
  Our findings suggest that MPE may be driven by a Warburg metabolic phenotype. The key enzymes promoting the Warburg phenotype: HK2, PKM2, and PDK are targetable by small-molecule inhibitors/activators, and should be considered for evaluation in future clinical trials for MPE.
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mack
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sameer
authors.initials: S
authors.lastname: Agnihotri
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kelsey C
authors.initials: KC
authors.lastname: Bertrand
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shih
authors.affiliation: Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Germany. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nadia
authors.initials: N
authors.lastname: Hill
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Kory
authors.initials: K
authors.lastname: Zayne
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Barszczyk
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Thompson
authors.affiliation: Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Germany. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.affiliation: Pediatric Neurosurgery, Catholic University Medical School, Gemelli Hospital, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Massimi
authors.affiliation: Department of Pathology University of Warsaw, Children's Memorial Health Institute University of Warsaw, Warsaw, Poland.
authors.forename: Wieslawa
authors.initials: W
authors.lastname: Grajkowska
authors.affiliation: Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario, Canada.
authors.forename: Boleslaw
authors.initials: B
authors.lastname: Lach
authors.affiliation: Departments of Neurology, Pediatrics, Neuro-Pathology and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California.
authors.forename: Nalin
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Departments of Neurology, Pediatrics, Neuro-Pathology and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sidney
authors.initials: S
authors.lastname: Croul
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.affiliation: Division of Pediatric Neuro-Oncology, German Cancer Research Center (DKFZ), Germany. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany. CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: Departments of Neurology, Pediatrics, Neuro-Pathology and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California.
authors.forename: Melike
authors.initials: M
authors.lastname: Pekmezci
authors.affiliation: Departments of Neurology, Pediatrics, Neuro-Pathology and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California.
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.affiliation: Departments of Neurology, Pediatrics, Neuro-Pathology and Neurosurgery, University of California, San Francisco, The Helen Diller Family Cancer Research Building, San Francisco, California.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Philips
authors.affiliation: Departments of Pediatrics and Human Genetics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.affiliation: Developmental & Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. mdtaylor@sickkids.ca.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000328:Adult; D000368:Aged; D056915:DNA Copy Number Variations / Q000235:genetics*; D004806:Ependymoma / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013116:Spinal Cord / Q000473:pathology; D013125:Spinal Neoplasms / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D006593:Hexokinase; D017346:Protein Serine-Threonine Kinases