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• W2793805945 abstract "Medulloblastoma ( MB ) is the most common malignant primary pediatric brain cancer. Among the most aggressive subtypes, Group 3 and Group 4 originate from stem/progenitor cells, frequently metastasize, and often display the worst prognosis, yet we know the least about the molecular mechanisms driving their progression. Here, we show that the transcription factor orthodenticle homeobox 2 ( OTX 2) promotes self‐renewal while inhibiting differentiation in vitro and increases tumor initiation from MB stem/progenitor cells in vivo . To determine how OTX 2 contributes to these processes, we employed complementary bioinformatic approaches to characterize the OTX 2 regulatory network and identified novel relationships between OTX 2 and genes associated with neuronal differentiation and axon guidance signaling in Group 3 and Group 4 MB stem/progenitor cells. In particular, OTX 2 levels were negatively correlated with semaphorin ( SEMA ) signaling, as expression of 9 SEMA pathway genes is upregulated following OTX 2 knockdown with some being potential direct OTX 2 targets. Importantly, this negative correlation was also observed in patient samples, with lower expression of SEMA 4D associated with poor outcome specifically in Group 4 tumors. Functional proof‐of‐principle studies demonstrated that increased levels of select SEMA pathway genes are associated with decreased self‐renewal and growth in vitro and in vivo and that RHO signaling, known to mediate the effects of SEMA genes, is contributing to the OTX 2 KD phenotype. Our study provides mechanistic insight into the networks controlled by OTX 2 in MB stem/progenitor cells and reveals novel roles for axon guidance genes and their downstream effectors as putative tumor suppressors in MB ." @default.
• W2793805945 created "2018-03-29" @default.
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• W2793805945 date "2018-03-01" @default.
• W2793805945 modified "2023-10-15" @default.
• W2793805945 title "Characterization of a novel OTX2-driven stem cell program in Group 3 and Group 4 medulloblastoma" @default.
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• W2793805945 doi "https://doi.org/10.1002/1878-0261.12177" @default.
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• W2793805945 hasPublicationYear "2018" @default.
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