Neural derivatives from human embryonic stem cells: a cellular and molecular model for studying the role of orthodenticle homeobox2 in medulloblastoma progression
| dc.contributor.author | Kaur, Ravinder | |
| dc.contributor.examiningcommittee | Nachtigal, Mark (Biochemistry and Medical Genetics) Karimi, Soheila (Physiology and Pathophysiology) Raouf, Afshin (Immunology) Eisenstat, David (University of Alberta) | en_US |
| dc.contributor.supervisor | Ogilvie, Tamra (Biochemistry and Medical Genetics) | en_US |
| dc.date.accessioned | 2016-10-31T18:54:54Z | |
| dc.date.available | 2016-10-31T18:54:54Z | |
| dc.date.issued | 2015-07-29 | en_US |
| dc.degree.discipline | Biochemistry and Medical Genetics | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor and is divided into 4 subtypes based on different genomic alterations and gene expression profiles. 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 upregulated 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 MBs. These trans-hENs also have >10-fold expression of OTX2. Therefore, we hypothesize that OTX2 has cell context-dependent functions in MB and using both normal and trans-hENs, we can delineate its specific roles in MB progression. Parallel experiments with MB cells revealed that OTX2 exerts inhibitory effects on hEN and sonic hedgehog (SHH) MB cells by regulating growth, self-renewal and migration in vitro and tumor growth in vivo. Overexpression of OTX2 was accompanied by a decrease in expression of pluripotent genes such as SOX2. This was supported by exogenous introduction of SOX2 in OTX2+ SHH MB and hENs that rescued the OTX2 induced cellular deficits including self-renewal and cell migration. In contrast, OTX2 is oncogenic and promotes self-renewal of trans-hENs and Group 3 and 4 MBs by modulating expression of genes related to neurodevelopment and axonal guidance. OTX2 may play a central role in regulating the balance between self-renewal and differentiation in these aggressive MB cells. Our studies underscore the value of hESC derivatives as alternatives to cell lines and heterogeneous patient samples for investigating the contribution of key developmental regulators to MB progression. Using the neural derivatives of hESCs, we have demonstrated a novel role for OTX2 in self-renewal and migration of hENs and MB cells. Moreover, our results reveal a cell context-dependent link between OTX2 and pluripotent genes. The association between OTX2 and axonal guidance genes is important for its oncogenic role and may potentially be exploited for managing drug resistant stem cell and highly motile cellular populations in the most aggressive Group 3 and 4 MB subtypes. | en_US |
| dc.description.note | February 2017 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/31914 | |
| dc.language.iso | eng | en_US |
| dc.publisher | The company of Biologists Ltd | en_US |
| dc.rights | open access | en_US |
| dc.subject | Human embryonic stem cells, Neural precursors, Medulloblastoma, OTX2 | en_US |
| dc.title | Neural derivatives from human embryonic stem cells: a cellular and molecular model for studying the role of orthodenticle homeobox2 in medulloblastoma progression | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | yes | en_US |