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OTX2 exhibits cell context-dependent effects on cellular and molecular properties of human embryonic neural precursors and medulloblastoma cells
- Source :
- Disease Models & Mechanisms, Disease Models & Mechanisms, Vol 8, Iss 10, Pp 1295-1309 (2015)
- Publication Year :
- 2015
- Publisher :
- The Company of Biologists, 2015.
-
Abstract
- Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is currently divided into four subtypes based on different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. This extensive heterogeneity has made it difficult to assess the functional relevance of genes to malignant progression. For example, expression of the transcription factor Orthodenticle homeobox2 (OTX2) is frequently dysregulated in multiple MB variants; however, its role may be subtype specific. We recently demonstrated that neural precursors derived from transformed human embryonic stem cells (trans-hENs), but not their normal counterparts (hENs), resemble Groups 3 and 4 MB in vitro and in vivo. Here, we tested the utility of this model system as a means of dissecting the role of OTX2 in MB using gain- and loss-of-function studies in hENs and trans-hENs, respectively. Parallel experiments with MB cells revealed that OTX2 exerts inhibitory effects on hEN and SHH MB cells by regulating growth, self-renewal and migration in vitro and tumor growth in vivo. This was accompanied by decreased expression of pluripotent genes, such as SOX2, and was supported by overexpression of SOX2 in OTX2+ SHH MB and hENs that resulted in significant rescue of self-renewal and cell migration. By contrast, OTX2 is oncogenic and promotes self-renewal of trans-hENs and Groups 3 and 4 MB independent of pluripotent gene expression. Our results demonstrate a novel role for OTX2 in self-renewal and migration of hENs and MB cells and reveal a cell-context-dependent link between OTX2 and pluripotent genes. Our study underscores the value of human embryonic stem cell derivatives as alternatives to cell lines and heterogeneous patient samples for investigating the contribution of key developmental regulators to MB progression.<br />Summary: Human embryonic stem cell neural derivatives can be used to model the molecular and cellular properties of medulloblastoma.
- Subjects :
- Pluripotent Stem Cells
Cell Survival
Human Embryonic Stem Cells
Neuroscience (miscellaneous)
lcsh:Medicine
Down-Regulation
Medicine (miscellaneous)
Models, Biological
General Biochemistry, Genetics and Molecular Biology
Neural Stem Cells
Immunology and Microbiology (miscellaneous)
SOX2
Cell Movement
Cell Line, Tumor
lcsh:Pathology
Humans
Gene Regulatory Networks
RNA, Messenger
Cell Self Renewal
Sonic hedgehog
Induced pluripotent stem cell
Cell Proliferation
Otx Transcription Factors
biology
Gene Expression Profiling
SOXB1 Transcription Factors
lcsh:R
Wnt signaling pathway
Cell migration
Embryonic stem cell
Molecular biology
Neural stem cell
3. Good health
Cell biology
Brain tumor modeling
Gene Expression Regulation, Neoplastic
Gene expression profiling
hESCs
Gene Knockdown Techniques
biology.protein
Transcriptome
lcsh:RB1-214
Research Article
OTX2
Medulloblastoma
Subjects
Details
- ISSN :
- 17548411 and 17548403
- Database :
- OpenAIRE
- Journal :
- Disease Models & Mechanisms
- Accession number :
- edsair.doi.dedup.....d9be78dfc6fabb743c749aebce8c42fc