Abstract
ABSTRACTMedulloblastoma (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.
Highlights
Embryonal tumors of the central nervous system constitute a group of highly malignant cancers that manifest early during development and include medulloblastoma (MB), primitive neuro-ectodermal tumors and atypical rhabdoid/teratoid tumor (Mehta et al, 2011)
By employing human embryonic stem cell (hESC) derivatives as a powerful cell resource for investigating key biological questions related to MB, the authors sought to evaluate the role of orthodenticle homeobox 2 (OTX2) in MB cells using gain- and lossof-function approaches both in vitro and in vivo
It was found that OTX2 exerts inhibitory effects on human embryonic neural precursors and in Sonic Hedgehog (SHH) MB cells by decreasing self-renewal, migration and growth, probably through regulation of pluripotent genes, such as SOX2
Summary
Embryonal tumors of the central nervous system constitute a group of highly malignant cancers that manifest early during development and include medulloblastoma (MB), primitive neuro-ectodermal tumors and atypical rhabdoid/teratoid tumor (Mehta et al, 2011). MB consists of four distinct subtypes exhibiting different genomic alterations, gene expression profiles and response to treatment: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4 (Taylor et al, 2012). This had led to the identification of many subgroup-specific mutated genes (Jones et al, 2012; Northcott et al, 2012; Pugh et al, 2012; Robinson et al, 2012); the functional role of both mutated and differentially expressed genes is poorly understood. Complementary human models are still needed to both verify and identify the functional relevance of specific genes to pediatric neural tumor progression
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