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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [scRNA-seq]

ABSTRACT: scRNA-seq was performed to evaluate the OTX2-PAX3-mTOR signalling axis at the single cell level in heterogeneous Group 3 MB tumorspheres

ORGANISM(S): Homo sapiens

PROVIDER: GSE137758 | GEO | 2020/06/11

REPOSITORIES: GEO

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [ChIP-seq]

Project description:We evaluated changes in active and repressive histone modifications following the silencing of OTX2 in Group 3 medulloblastoma tumorspheres

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate.

Project description:OTX2 is a potent oncogene that promotes tumor growth in Group 3 medulloblastoma. However, the mechanisms by which OTX2 represses neural differentiation are not well characterized. Here, we perform extensive multiomic analyses to identify an OTX2 regulatory network that controls Group 3 medulloblastoma cell fate. OTX2 silencing modulates the repressive chromatin landscape, decreases levels of PRC2 complex genes and increases the expression of neurodevelopmental transcription factors including PAX3 and PAX6. Expression of PAX3 and PAX6 is significantly lower in Group 3 medulloblastoma patients and is correlated with reduced survival, yet only PAX3 inhibits self-renewal in vitro and increases survival in vivo. Single cell RNA sequencing of Group 3 medulloblastoma tumorspheres demonstrates expression of an undifferentiated progenitor program observed in primary tumors and characterized by translation/elongation factor genes. Identification of mTORC1 signaling as a downstream effector of OTX2-PAX3 reveals roles for protein synthesis pathways in regulating Group 3 medulloblastoma pathogenesis.

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [RNA-seq]

Project description:RNA-seq was carried out to evaluate the molecular mechanisms that contribute to the distinguishing effects of PAX3 and PAX6 GOF on Group 3 MB cells

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [ChIP-seq]

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [RNA-seq]

Project description:An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [RNA-seq]

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [scRNA-seq]

Project description:An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate [scRNA-seq]

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An OTX2-PAX3 signaling axis regulates Group 3 medulloblastoma cell fate

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-06-11 | GSE132558 | GEO

Characterization of a novel OTX2-driven self-renewal program in Group 3 and Group 4 medulloblastoma [expression]

Project description: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, as the names imply, we know the least about the molecular mechanisms driving their progression. Here, we show that the transcription factor orthodenticle homeobox 2 (OTX2) promotes self-renewal while inhibiting differentiation in vitro and increases tumor-initiating capacity from MB stem cell populations in vivo. Characterization of the OTX2 regulatory network revealed a novel relationship between OTX2 and genes associated with multiple axon guidance signaling pathways in Group 3 and Group 4 MB stem/progenitor cells. In particular, OTX2 levels were negatively correlated with semaphorin (SEMA) signaling, as expression of 9 SEMA pathway genes is upregulated following OTX2 knockdown with some being potential direct OTX2 targets. Importantly, this negative correlation between OTX2 and SEMA pathway genes was also observed in patient samples, with lower expression of SEMA4D associated with poor outcome in Group 3 and 4 tumors. Functional studies using established and newly derived MB cell lines demonstrated that increased levels of SEMA pathway genes are associated with decreased self-renewal and growth, and that RHO signaling, known to mediate the effects of SEMA genes, is contributing to the OTX2 KD phenotype. Our study provides critical mechanistic insight into the networks controlled by OTX2 in self-renewing MB cells and reveals novel roles for axon guidance genes and their downstream effectors as putative tumor suppressors and therapeutic targets in Group 3 and Group 4 MB.

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Characterization of a novel OTX2-driven self-renewal program in Group 3 and Group 4 medulloblastoma [ChIP-seq]

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