1. Functional genomics identifies drivers of medulloblastoma dissemination.
- Author
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Mumert M, Dubuc A, Wu X, Northcott PA, Chin SS, Pedone CA, Taylor MD, and Fults DW
- Subjects
- Animals, Cell Line, Cerebellar Neoplasms metabolism, Cyclin-Dependent Kinases genetics, Cyclin-Dependent Kinases metabolism, DNA Transposable Elements genetics, Female, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Humans, Immunohistochemistry, Intermediate Filament Proteins genetics, Intermediate Filament Proteins metabolism, LIM-Homeodomain Proteins genetics, LIM-Homeodomain Proteins metabolism, Male, Medulloblastoma metabolism, Meninges metabolism, Meninges pathology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Mutagenesis, Insertional, Neoplasm Metastasis, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Nestin, Oligonucleotide Array Sequence Analysis, Oncogene Protein p21(ras) genetics, Oncogene Protein p21(ras) metabolism, Spinal Cord metabolism, Spinal Cord pathology, Transcription Factors genetics, Transcription Factors metabolism, Cyclin-Dependent Kinase-Activating Kinase, Cerebellar Neoplasms genetics, Gene Expression Profiling methods, Genomics methods, Medulloblastoma genetics
- 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., (©2012 AACR.)
- Published
- 2012
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