Microenvironment-Driven Dynamic Chromatin Changes in Glioblastoma Recapitulate Early Neural Development at Single-Cell Resolution.
Microenvironment-Driven Dynamic Chromatin Changes in Glioblastoma Recapitulate Early Neural Development at Single-Cell Resolution.
复制标题
胶质母细胞瘤中微环境驱动的动态染色质变化以单细胞分辨率重现早期神经发育。
DOI：
10.1158/0008-5472.can-22-2872
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发表时间：
2023
期刊：
影响因子：
11.2
通讯作者：
Fine,HowardA
中科院分区：
文献类型：
--
作者：
Pine,AllisonR;Cirigliano,StefanoM;Singhania,Richa;Nicholson,James;daSilva,Bárbara;Leslie,ChristinaS;Fine,HowardA
肿瘤微环境是重现人类原发胶质母细胞瘤(GBM)瘤内异质性和细胞状态可塑性所必需的。传统的模型不能准确地概括GBM细胞状态的光谱，阻碍了对这些状态的潜在转录调控的阐明。使用我们的胶质母细胞瘤脑器官模型，我们分析了五个患者来源的胶质瘤干细胞系中28,040个单细胞的染色质可及性。在肿瘤-正常宿主细胞相互作用的背景下，成对的表观基因组和转录体的整合被用来探索个体GBM细胞状态下的基因调控网络，这种方式在其他体外模型中是不可能的。这些分析确定了GBM细胞状态的表观遗传学基础，并描述了染色质的动态变化，这让人想起作为GBM细胞状态转换基础的早期神经发育。尽管肿瘤之间有很大的差异，但可以观察到由神经前体样细胞和外径向神经胶质样细胞组成的共同细胞室。综上所述，这些结果揭示了GBM的转录调控程序，并为广泛的遗传异质性GBM提供了新的治疗靶点。意义单细胞分析阐明了胶质母细胞瘤细胞状态的染色质景观和转录调控，并确定了放射状胶质细胞样群，为扰乱细胞状态和提高治疗效果提供了潜在的靶点。
The tumor microenvironment is necessary for recapitulating the intratumoral heterogeneity and cell state plasticity found in human primary glioblastoma (GBM). Conventional models do not accurately recapitulate the spectrum of GBM cellular states, hindering elucidation of the underlying transcriptional regulation of these states. Using our glioblastoma cerebral organoid model, we profiled the chromatin accessibility of 28,040 single cells in five patient-derived glioma stem cell lines. Integration of paired epigenomes and transcriptomes within the context of tumor-normal host cell interactions was used to probe the gene-regulatory networks underlying individual GBM cellular states in a way not readily possible in otherin vitromodels. These analyses identified the epigenetic underpinnings of GBM cellular states and characterized dynamic chromatin changes reminiscent of early neural development that underlie GBM cell state transitions. Despite large differences between tumors, a shared cellular compartment made up of neural progenitor-like cells and outer radial glia–like cells was observed. Together, these results shed light on the transcriptional regulation program in GBM and offer novel therapeutic targets across a broad range of genetically heterogenous GBMs.SignificanceSingle-cell analyses elucidate the chromatin landscape and transcriptional regulation of glioblastoma cellular states and identify a radial glia–like population, providing potential targets to disrupt cell states and improve therapeutic efficacy.