Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells
Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells
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DOI：
10.1101/gad.321968.118
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发表时间：
2019-05-01
影响因子：
10.5
通讯作者：
Dirks, Peter B.
中科院分区：
文献类型：
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作者：
Rajakulendran, Nishani;Rowland, Katherine J.;Dirks, Peter B.
发育信号转导通路的行为是不稳定的，在系统和疾病类型中具有依赖于环境的作用。胶质母细胞瘤（GBM）是预后最差的原发性脑癌，与发育系统非常相似，但这些生长过程尚未在治疗上加以利用，可能部分原因是在这些肿瘤中观察到的极端细胞和遗传异质性。Wnt/β连环蛋白信号在GBM干细胞（GSC）更新和命运决定中的作用仍然存在争议。在这里，我们报告了Wnt/β连环蛋白信号传导在指导细胞命运规范和更新中的特定作用。原代GBM衍生干细胞的一个子集需要Wnt蛋白进行自我更新，并且该子集特别依赖于Wnt/β连环蛋白信号传导来增强异种移植模型中的肿瘤负荷。在原位Wnt报告基因模型中，Wnt（hi）GBM细胞（表现出高水平的β连环蛋白信号传导）是一个更快循环、高度自我更新的干细胞库。相比之下，Wnt（lo）细胞（具有低水平的信号传导）是较慢的循环，并且具有降低的自我更新潜力。双重抑制表达高水平前神经转录因子ASCL 1的GSC中的Wnt/β连环蛋白和Notch信号传导导致稳健的神经元分化并抑制克隆形成潜力。我们的工作确定了Wnt调节靶向干细胞分化和GBM异质性自我更新的新背景，值得在治疗上进一步探索。
Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/beta catenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/beta catenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/beta catenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnt(hi) GBM cells (which exhibit high levels of beta catenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wnt(lo) cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/beta catenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.