title: Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.
abstract: The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Phoenix
authors.affiliation: Li Ka Shing Centre, CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, England.
authors.forename: Deanna M
authors.initials: DM
authors.lastname: Patmore
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Boop
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Nidal
authors.initials: N
authors.lastname: Boulos
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Megan O
authors.initials: MO
authors.lastname: Jacus
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Yogesh T
authors.initials: YT
authors.lastname: Patel
authors.affiliation: Department of Tumor Cell Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
authors.affiliation: Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: David
authors.initials: D
authors.lastname: Finkelstein
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Goumnerova
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University Medical Center, 1201 Welch Road, Stanford, CA 94305, USA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Perreault
authors.affiliation: Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wadhwa
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University Medical Center, 1201 Welch Road, Stanford, CA 94305, USA; Department of Neurosurgery, Stanford University Medical Center, 1201 Welch Road, Stanford, CA 94305, USA.
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.affiliation: Li Ka Shing Centre, CRUK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, England. Electronic address: richard.gilbertson@cruk.cam.ac.uk.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D002352:Carrier Proteins / Q000502:physiology; D002528:Cerebellar Neoplasms / Q000098:blood supply / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000648:ultrastructure; D056726:Genetic Association Studies; D005822:Genetic Vectors / Q000627:therapeutic use; D005838:Genotype; D051272:Glucose Transporter Type 1 / Q000502:physiology; D006801:Humans; D008527:Medulloblastoma / Q000098:blood supply / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000502:physiology; D019899:Paracrine Communication / Q000187:drug effects; D020286:Pericytes / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019108:Tight Junctions / Q000648:ultrastructure; D014161:Transduction, Genetic; D014750:Vincristine / Q000493:pharmacokinetics / Q000627:therapeutic use; D051153:Wnt Proteins / Q000235:genetics / Q000502:physiology; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D051272:Glucose Transporter Type 1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C486771:PLVAP protein, human; D011993:Recombinant Fusion Proteins; C495677:SLC2A1 protein, human; C092778:WNT7A protein, human; D051153:Wnt Proteins; D014750:Vincristine