OTX2 exhibits cell-context-dependent effects on cellular and molecular properties of human embryonic neural precursors and medulloblastoma cells.
OTX2 exhibits cell-context-dependent effects on cellular and molecular properties of human embryonic neural precursors and medulloblastoma cells.
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DOI：
10.1242/dmm.020594
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发表时间：
2015-10-01
影响因子：
4.3
通讯作者：
Werbowetski-Ogilvie T
中科院分区：
文献类型：
--
作者：
Kaur R;Aiken C;Morrison LC;Rao R;Del Bigio MR;Rampalli S;Werbowetski-Ogilvie T
髓母细胞瘤（MB）是最常见的恶性原发性儿科脑肿瘤，目前根据不同的基因组改变、基因表达谱和治疗反应分为四种亚型：WNT、Sonic Hedgehog（SHH）、第3组和第4组。这种广泛的异质性使得难以评估基因与恶性进展的功能相关性。例如，转录因子Orthodenticle homeobox 2（OTX 2）的表达在多种MB变体中经常失调;然而，其作用可能是亚型特异性的。我们最近证明，神经前体细胞来源于转化的人胚胎干细胞（trans-hENs），但不是他们的正常对应物（hENs），类似于组3和4 MB在体外和体内。在这里，我们测试了这个模型系统的效用，作为一种手段，剖析的作用，OTX 2在MB中使用的增益和损失的功能研究，在hEN和trans-hEN，分别。MB细胞的平行实验显示，OTX 2通过调节体外生长、自我更新和迁移以及体内肿瘤生长对hEN和SHH MB细胞发挥抑制作用。这伴随着多能基因如SOX 2的表达降低，并且得到了SOX 2在OTX 2 + SHH MB和hEN中的过表达的支持，这导致自我更新和细胞迁移的显著拯救。相比之下，OTX 2是致癌的，并促进trans-hEN和组3和4 MB的自我更新，而不依赖于多能基因表达。我们的研究结果证明了OTX 2在hEN和MB细胞的自我更新和迁移中的新作用，并揭示了OTX 2和多能基因之间的细胞环境依赖性联系。我们的研究强调了人类胚胎干细胞衍生物作为细胞系和异质性患者样本的替代品的价值，用于研究关键发育调节因子对MB进展的贡献。总结：人胚胎干细胞神经衍生物可用于髓母细胞瘤的分子和细胞特性建模。
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. Summary: Human embryonic stem cell neural derivatives can be used to model the molecular and cellular properties of medulloblastoma.