Liu Jun, Wang Xiaoying, Chen Ann T, Gao Xingchun, Himes Benjamin T, Zhang Hongyi, Chen Zeming, Wang Jianhui, Sheu Wendy C, Deng Gang, Xiao Yang, Zou Pan, Zhang Shenqi, Liu Fuyao, Zhu Yong, Fan Rong, Patel Toral R, Saltzman W Mark, Zhou Jiangbing
Department of Neurosurgery, Yale University, New Haven, CT, 06511, USA.
Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, 214122, China.
Nat Commun. 2022 Apr 22;13(1):2196. doi: 10.1038/s41467-022-29884-3.
Glioblastoma (GBM) is a deadly disease without effective treatment. Because glioblastoma stem cells (GSCs) contribute to tumor resistance and recurrence, improved treatment of GBM can be achieved by eliminating GSCs through inducing their differentiation. Prior efforts have been focused on studying GSC differentiation towards the astroglial lineage. However, regulation of GSC differentiation towards the neuronal and oligodendroglial lineages is largely unknown. To identify genes that control GSC differentiation to all three lineages, we performed an image-based genome-wide RNAi screen, in combination with single-cell RNA sequencing, and identified ZNF117 as a major regulator of GSC differentiation. Using patient-derived GSC cultures, we show that ZNF117 controls GSC differentiation towards the oligodendroglial lineage via the Notch pathway. We demonstrate that ZNF117 is a promising target for GSC differentiation therapy through targeted delivery of CRISPR/Cas9 gene-editing nanoparticles. Our study suggests a direction to improve GBM treatment through differentiation of GSCs towards various lineages.
胶质母细胞瘤（GBM）是一种缺乏有效治疗方法的致命疾病。由于胶质母细胞瘤干细胞（GSCs）会导致肿瘤耐药和复发，因此通过诱导GSCs分化来消除它们，有望改善GBM的治疗效果。此前的研究主要集中在GSCs向星形胶质细胞谱系的分化上。然而，GSCs向神经元和少突胶质细胞谱系分化的调控机制在很大程度上尚不清楚。为了确定控制GSCs向这三种谱系分化的基因，我们结合单细胞RNA测序，进行了基于图像的全基因组RNA干扰筛选，并确定ZNF117是GSCs分化的主要调节因子。利用患者来源的GSCs培养物，我们发现ZNF117通过Notch信号通路控制GSCs向少突胶质细胞谱系的分化。我们证明，通过靶向递送CRISPR/Cas9基因编辑纳米颗粒，ZNF117是GSCs分化治疗的一个有前景的靶点。我们的研究为通过使GSCs向不同谱系分化来改善GBM治疗提供了一个方向。
