title: Distinct neural stem cell populations give rise to disparate brain tumors in response to N-MYC.
abstract: The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-myc(T58A) into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-myc(WT) NSCs was insufficient for tumor formation. N-myc(T58A) cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal.
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA; Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-75185 Uppsala, Sweden. Electronic address: fredrik.swartling@igp.uu.se.
authors.forename: Fredrik J
authors.initials: FJ
authors.lastname: Swartling
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-75185 Uppsala, Sweden.
authors.forename: Vasil
authors.initials: V
authors.lastname: Savov
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Anders I
authors.initials: AI
authors.lastname: Persson
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Chen
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hackett
authors.affiliation: The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Grimmer
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Lau
authors.affiliation: The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.
authors.forename: Louis
authors.initials: L
authors.lastname: Chesler
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.affiliation: The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.affiliation: University of California, Departments of Neurology, Pathology, Pediatrics, Neurosurgery, Brain Tumor Research Center and Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94158, USA. Electronic address: waweiss@gmail.com.
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001933:Brain Stem / Q000196:embryology / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002528:Cerebellar Neoplasms / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000196:embryology / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008527:Medulloblastoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation; D000071447:N-Myc Proto-Oncogene Protein; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D018242:Neuroectodermal Tumors, Primitive / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000196:embryology / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D013997:Time Factors; D014161:Transduction, Genetic; D000075746:Zinc Finger Protein Gli2
chemical_list: D015415:Biomarkers; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C000715470:MAS1 protein, human; C459801:MYCN protein, human; C571825:MYCN protein, mouse; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; C509239:SHH protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C465570:Shh protein, mouse; C527933:Sox9 protein, mouse; D000075746:Zinc Finger Protein Gli2