| Summary: | Summary: Malignant brain tumors are the leading cause of cancer-related deaths in children. Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are particularly aggressive embryonal tumors of unknown cellular origin. Recent genomic studies have classified CNS-PNETs into molecularly distinct subgroups that promise to improve diagnosis and treatment; however, the lack of cell- or animal-based models for these subgroups prevents testing of rationally designed therapies. Here, we show that a subset of CNS-PNETs co-express oligoneural precursor cell (OPC) markers OLIG2 and SOX10 with coincident activation of the RAS/MAPK (mitogen-activated protein kinase) pathway. Modeling NRAS activation in embryonic OPCs generated malignant brain tumors in zebrafish that closely mimic the human oligoneural/NB-FOXR2 CNS-PNET subgroup by histology and comparative oncogenomics. The zebrafish CNS-PNET model was used to show that MEK inhibitors selectively eliminate Olig2+/Sox10+ CNS-PNET tumors in vivo without impacting normal brain development. Thus, MEK inhibitors represent a promising rationally designed therapy for children afflicted with oligoneural/NB-FOXR2 CNS-PNETs. : Modzelewska et al. generate a zebrafish model of CNS-PNET driven by NRAS activation in Olig2+/Sox10+ oligoneural precursor cells. Molecular and genomic analyses show that the zebrafish brain tumors closely resemble the oligoneural/NB-FOXR2 CNS-PNET subgroup. Finally, an embryonic brain tumor transplantation assay designed to screen drugs shows that MEK inhibitors can eradicate these tumors in vivo. Keywords: pediatric brain tumors, CNS-PNET, zebrafish, oligodendrocyte, embryonal, SOX10, OLIG2, RAS, MAPK, MEK inhibitors
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