Li Jinwei, Long Shengrong, Zhang Yang, Yu Shuangqi, Xu Hongyu, Liang Rui, Liu Quan, Zhang Jinnan, Li Xiang, Fu Yixin, Xin Tao, Wang Yinyan
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, 610000, China.
Acta Neuropathol Commun. 2025 Jun 7;13(1):127. doi: 10.1186/s40478-025-02036-6.
Gliomas, particularly glioblastomas, are highly malignant brain tumors with high recurrence rates and poor prognosis. Despite advances in treatment, recurrence remains a major challenge. Epithelial-mesenchymal transition (EMT) plays a key role in tumor invasion and recurrence. This study explores the transcriptional and regulatory mechanisms driving glioma recurrence, focusing on mesenchymal-like (MES-like) subpopulations. Single-nucleus RNA sequencing was performed on 52 IDH wild-type GBM specimens, including 26 primary and 26 recurrent tumors. Spatial transcriptomics data were also incorporated. Tumor subpopulations were identified through gene regulatory network analysis, copy number variation detection, and nonnegative matrix factorization. Functional validation was conducted using gene knockdown experiments, followed by xenograft studies. We discovered novel MES-like subpopulations in recurrent GBM enriched with EMT-related genes like EGR1 and SERPINE1. These subpopulations exhibited increased transcriptional activity and were associated with poor prognosis and invasiveness. Knockdown of SERPINE1 significantly reduced cell proliferation and migration. Spatial transcriptomics showed MES-like cells concentrated at the tumor margins, highlighting their role in invasion and recurrence. MES-like subpopulations, driven by EGR1 and SERPINE1, are critical in GBM. Targeting these regulators could offer new therapeutic strategies to reduce glioma recurrence and improve outcomes.
神经胶质瘤，尤其是胶质母细胞瘤，是高度恶性的脑肿瘤，复发率高且预后不良。尽管治疗取得了进展，但复发仍然是一个重大挑战。上皮-间质转化（EMT）在肿瘤侵袭和复发中起关键作用。本研究探讨驱动神经胶质瘤复发的转录和调控机制，重点关注间充质样（MES样）亚群。对52个异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤标本进行了单核RNA测序，包括26个原发性肿瘤和26个复发性肿瘤。还纳入了空间转录组学数据。通过基因调控网络分析、拷贝数变异检测和非负矩阵分解来识别肿瘤亚群。使用基因敲低实验进行功能验证，随后进行异种移植研究。我们在复发性胶质母细胞瘤中发现了新的MES样亚群，其富含EGR1和SERPINE1等与EMT相关的基因。这些亚群表现出增加的转录活性，并与预后不良和侵袭性相关。敲低SERPINE1可显著降低细胞增殖和迁移。空间转录组学显示MES样细胞集中在肿瘤边缘，突出了它们在侵袭和复发中的作用。由EGR1和SERPINE1驱动的MES样亚群在胶质母细胞瘤中至关重要。靶向这些调节因子可为降低神经胶质瘤复发和改善预后提供新的治疗策略。
