title: Functional genomics identifies drivers of medulloblastoma dissemination.
abstract: Medulloblastomas are malignant brain tumors that arise in the cerebellum in children and disseminate via the cerebrospinal fluid to the leptomeningeal spaces of the brain and spinal cord. Challenged by the poor prognosis for patients with metastatic dissemination, pediatric oncologists have developed aggressive treatment protocols, combining surgery, craniospinal radiation, and high-dose chemotherapy, that often cause disabling neurotoxic effects in long-term survivors. Insights into the genetic control of medulloblastoma dissemination have come from transposon insertion mutagenesis studies. Mobilizing the Sleeping Beauty transposon in cerebellar neural progenitor cells caused widespread dissemination of typically nonmetastatic medulloblastomas in Patched(+/-) mice, in which Shh signaling is hyperactive. Candidate metastasis genes were identified by sequencing the insertion sites and then mapping these sequences back to the mouse genome. To determine whether genes located at transposon insertion sites directly caused medulloblastomas to disseminate, we overexpressed candidate genes in Nestin(+) neural progenitors in the cerebella of mice by retroviral transfer in combination with Shh. We show here that ectopic expression of Eras, Lhx1, Ccrk, and Akt shifted the in vivo growth characteristics of Shh-induced medulloblastomas from a localized pattern to a disseminated pattern in which tumor cells seeded the leptomeningeal spaces of the brain and spinal cord.
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Mumert
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Wu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Steven S
authors.initials: SS
authors.lastname: Chin
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Pedone
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Fults
mesh_terms: D000818:Animals; D002460:Cell Line; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004251:DNA Transposable Elements / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D023281:Genomics / Q000379:methods*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism; D008578:Meninges / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D020411:Oligonucleotide Array Sequence Analysis; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D004251:DNA Transposable Elements; C474774:ERas protein, human; D053823:Hedgehog Proteins; D007381:Intermediate Filament Proteins; C085473:LHX1 protein, human; D060850:LIM-Homeodomain Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C509239:SHH protein, human; D014157:Transcription Factors; D018844:Cyclin-Dependent Kinases; D015689:Oncogene Protein p21(ras); D000095043:Cyclin-Dependent Kinase-Activating Kinase