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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE132506 | GEO | 2020/06/11

REPOSITORIES: GEO

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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.

| S-EPMC7371715 | biostudies-literature

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

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

2020-06-11 | GSE137758 | GEO

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

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

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

| PRJNA548355 | ENA

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

2020-06-11 | GSE132269 | GEO

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]

| PRJNA548193 | ENA

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

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

| PRJNA547350 | ENA

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]

| PRJNA566451 | ENA

BioID HEK293T PAX3-FOXO1 proximity labelling

Project description:PAX3-FOXO1 is a fusion transcription factor that is the main driver of tumorigenesis leading to the development of alveolar rhabdomyosarcoma (aRMS). Since aRMS cells are addicted to PAX3-FOXO1 activity, the fusion protein also represents a major target for therapeutic interference, which is however challenging as transcription factors usually cannot be inhibited directly by small molecules. Hence, characterization of the biology of PAX3-FOXO1 might lead to the discovery of new possibilities for an indirect inhibition of its activity. Here, our goal was to characterize the proteomic neighborhood of PAX3-FOXO1 and to find candidates potentially affecting its activity and tumor cell viability. Towards this aim, we expressed BirA fused versions of PAX3-FOXO1 (N- and C-terminal) in HEK293T cells under presence of biotin. In the control setup, we expressed the BirA enzyme alone. After Streptavidin purification of biotinylated proteins, we performed mass spectrometry and quantified relative abundances compared to control conditions. This enabled us to determine PAX3-FOXO1 proximal proteins, which we investigated further in orthogonal endogenous systems.

2021-09-16 | PXD022187 | Pride

Characterization of a novel OTX2-driven stem cell program in Group 3 and Group 4 medulloblastoma.

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 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 initiation from MB stem/progenitor cells in vivo. To determine how OTX2 contributes to these processes, we employed complementary bioinformatic approaches to characterize the OTX2 regulatory network and identified novel relationships between OTX2 and genes associated with neuronal differentiation and axon guidance signaling 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 was also observed in patient samples, with lower expression of SEMA4D 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 OTX2 KD phenotype. Our study provides mechanistic insight into the networks controlled by OTX2 in MB stem/progenitor cells and reveals novel roles for axon guidance genes and their downstream effectors as putative tumor suppressors in MB.

| S-EPMC5891039 | biostudies-literature

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