Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in glioblastoma
Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in glioblastoma
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DOI：
10.1038/s43018-020-00150-z
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发表时间：
2021-02-01
期刊：
影响因子：
22.7
通讯作者：
Piccolo, Stefano
中科院分区：
文献类型：
--
作者：
Castellan, Martina;Guarnieri, Alberto;Piccolo, Stefano
胶质母细胞瘤（GBM）是一种毁灭性的人类恶性肿瘤。GBM干细胞样细胞（GSC）驱动肿瘤的发生和发展。然而，在患者中定义GSC在其天然状态下的分子决定因素仍然知之甚少。在这里，我们使用单细胞数据集并在GBM的分化层次的顶点鉴定GSC。通过重建GSC的调控网络，我们确定了雅普/TAZ共激活因子作为这种细胞状态的主要调控因子，而与GBM亚型无关。需要雅普/TAZ在多个致癌病变下游的原代细胞中设置GSC特性，并且在不同小鼠和人GBM模型中是体内肿瘤起始和维持所需的。雅普/TAZ作为GSC分化的主要障碍，它们的抑制不可逆地将分化的GBM细胞锁定在非致瘤状态，阻止GSC样细胞的可塑性和再生。因此，GSC的身份与GBM多方面生物学中整合遗传学和微环境输入的关键分子枢纽有关。Piccolo及其同事进行了整合的单细胞分析，并确定雅普/TAZ对胶质瘤干细胞分化的调控是肿瘤维持的核心依赖。
Glioblastoma (GBM) is a devastating human malignancy. GBM stem-like cells (GSCs) drive tumor initiation and progression. Yet the molecular determinants defining GSCs in their native state in patients remain poorly understood. Here we used single-cell datasets and identified GSCs at the apex of the differentiation hierarchy of GBM. By reconstructing the GSCs' regulatory network, we identified the YAP/TAZ coactivators as master regulators of this cell state, irrespectively of GBM subtypes. YAP/TAZ are required to install GSC properties in primary cells downstream of multiple oncogenic lesions and are required for tumor initiation and maintenance in vivo in different mouse and human GBM models. YAP/TAZ act as main roadblock of GSC differentiation, and their inhibition irreversibly locks differentiated GBM cells into a nontumorigenic state, preventing plasticity and regeneration of GSC-like cells. Thus, GSC identity is linked to a key molecular hub integrating genetics and microenvironmental inputs within the multifaceted biology of GBM.Piccolo and colleagues perform integrated single-cell analyses and identify YAP/TAZ regulation of glioma stem cell differentiation as a core dependency for tumor maintenance.