title: Pleiotropic role for MYCN in medulloblastoma.
abstract: Medulloblastoma (MB) is the most common malignant brain tumor of childhood. Sonic Hedgehog (SHH) signaling drives a minority of MB, correlating with desmoplastic pathology and favorable outcome. The majority, however, arises independently of SHH and displays classic or large cell anaplastic (LCA) pathology and poor prognosis. To identify common signaling abnormalities, we profiled mRNA, demonstrating misexpression of MYCN in the majority of human MB and negligible expression in normal cerebella. We clarified a role in pathogenesis by targeting MYCN (and luciferase) to cerebella of transgenic mice. MYCN-driven MB showed either classic or LCA pathologies, with Shh signaling activated in approximately 5% of tumors, demonstrating that MYCN can drive MB independently of Shh. MB arose at high penetrance, consistent with a role for MYCN in initiation. Tumor burden correlated with bioluminescence, with rare metastatic spread to the leptomeninges, suggesting roles for MYCN in both progression and metastasis. Transient pharmacological down-regulation of MYCN led to both clearance and senescence of tumor cells, and improved survival. Targeted expression of MYCN thus contributes to initiation, progression, and maintenance of MB, suggesting a central role for MYCN in pathogenesis.
authors.affiliation: University of California at San Francisco, San Francisco, California 94158, USA.
authors.forename: Fredrik J
authors.initials: FJ
authors.lastname: Swartling
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Grimmer
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hackett
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Qi-Wen
authors.initials: QW
authors.lastname: Fan
authors.forename: David D
authors.initials: DD
authors.lastname: Goldenberg
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lau
authors.forename: Selma
authors.initials: S
authors.lastname: Masic
authors.forename: Kim
authors.initials: K
authors.lastname: Nguyen
authors.forename: Slava
authors.initials: S
authors.lastname: Yakovenko
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Zhe
authors.forename: Heather C Flynn
authors.initials: HC
authors.lastname: Gilmer
authors.forename: Rodney
authors.initials: R
authors.lastname: Collins
authors.forename: Mai
authors.initials: M
authors.lastname: Nagaoka
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Scott R
authors.initials: SR
authors.lastname: Vandenberg
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Kohichi
authors.initials: K
authors.lastname: Tanaka
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism; D015536:Down-Regulation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D027322:Amino Acid Transport System X-AG; D053823:Hedgehog Proteins; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins