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

Nature Communications
Jamie ZagozewskiTamra E Werbowetski-Ogilvie

Abstract

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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Citations

Mar 16, 2021·Frontiers in Cell and Developmental Biology·Lars CustersJarno Drost

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Datasets Mentioned

BETA
GSE92585

Methods Mentioned

BETA
immunoprecipitation
flow cytometry
xenografts
xenograft
RNA-seq
scRNA-seq
PCR
PCA

Clinical Trials Mentioned

NCT03434262
NCT04023669
NCT01878617

Software Mentioned

Seurat
PCA
R package Seurat
Seurat CellCycleScoring
MSigDb
edgeR
Partek® Genomics Suite®
GSEA
UMAP
bowtie2

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