Outer Radial Glia-like Cancer Stem Cells Contribute to Heterogeneity of Glioblastoma
Outer Radial Glia-like Cancer Stem Cells Contribute to Heterogeneity of Glioblastoma
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DOI：
10.1016/j.stem.2019.11.015
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发表时间：
2020-01-01
期刊：
影响因子：
23.9
通讯作者：
Kriegstein, Arnold Richard
中科院分区：
文献类型：
--
作者：
Bhaduri, Aparna;Di Lullo, Elizabeth;Kriegstein, Arnold Richard
胶质母细胞瘤是一种毁灭性的脑癌。为了确定可能阐明肿瘤侵袭驱动因素的肿瘤异质性方面，我们创建了胶质母细胞瘤肿瘤细胞图谱，其中癌细胞的单细胞转录组学映射到发育和成人大脑的参考框架上。我们发现，多种GSC亚型存在于一个单一的肿瘤。在这些GSC中，我们发现了一种类似于外放射神经胶质细胞（oRG）的侵袭性细胞群，这是一种扩展正常人类皮质中干细胞生态位的胎儿细胞类型。使用原发性切除肿瘤的实时延时成像，我们发现肿瘤衍生的oRG样细胞经历了以前仅在人类发育中观察到的特征性有丝分裂染色体易位行为，这表明发育程序的重新激活。此外，我们发现PTPRZ1介导有丝分裂染色体易位和胶质母细胞瘤肿瘤侵袭。这些数据表明，异质性GSC的存在可能是胶质母细胞瘤快速进展和侵袭的基础。
Glioblastoma is a devastating form of brain cancer. To identify aspects of tumor heterogeneity that may illuminate drivers of tumor invasion, we created a glioblastoma tumor cell atlas with single-cell transcriptomics of cancer cells mapped onto a reference framework of the developing and adult human brain. We find that multiple GSC subtypes exist within a single tumor. Within these GSCs, we identify an invasive cell population similar to outer radial glia (oRG), a fetal cell type that expands the stem cell niche in normal human cortex. Using live time-lapse imaging of primary resected tumors, we discover that tumor-derived oRG-like cells undergo characteristic mitotic somal translocation behavior previously only observed in human development, suggesting a reactivation of developmental programs. In addition, we show that PTPRZ1 mediates both mitotic somal translocation and glioblastoma tumor invasion. These data suggest that the presence of heterogeneous GSCs may underlie glioblastoma's rapid progression and invasion.