Liang Muh-Lii, Chen Chun-Han, Lin Ya-Ching, Lin Yu-Chen, Liu Yun-Ru, Ding Yi-Huei, Chu Cheng-Ying, Hsieh Tsung-Han
Department of Neurosurgery, Mackay Memorial Hospital, Taipei, Taiwan, ROC.
Department of Medicine, Mackay Medical College, Taipei, Taiwan, ROC.
Cancer Gene Ther. 2025 Aug 14. doi: 10.1038/s41417-025-00955-z.
Glioblastoma multiforme (GBM) is an aggressive brain tumor partly driven by cancer stem cells (CSCs). Abemaciclib demonstrates the potential for treating GBM, although its mechanisms beyond RB phosphorylation are not fully understood. This study reveals that Abemaciclib diminishes GBM sphere formation by influencing EMT pathways via GSK3β-mediated regulation of CD44 and TCF7L2. Treatment with Abemaciclib significantly hindered sphere formation in GBM cells, and transcriptomic analysis indicated EMT pathways suppression. Mechanistically, Abemaciclib consistently lowered the expression of CD44 and TCF7L2 in both parental and sphere cells by inhibiting GSK3β phosphorylation. A pharmacological GSK3β inhibitor produced similar effects, reinforcing the existence of a GSK3β-CD44/TCF7L2 axis. Moreover, orthotopic xenografts confirmed reduced tumor growth and CD44 expression in vivo. Analyses of TCGA and CGGA datasets revealed that the mesenchymal GBM subtype (MES-GBM), linked with poor outcomes, exhibits elevated EMT gene expression. Treatment of MES-like LN229 cells with Abemaciclib resulted in decreased phosphorylation of GSK3β and reductions in EMT-related gene expression. Our findings highlight a novel EMT-suppressive action of Abemaciclib, illustrating its therapeutic potential for targeting the CSCs and for treating the MES-GBM. This research provides mechanistic insights and justification for repurposing Abemaciclib as targeted therapies for aggressive glioblastoma.
多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，部分由癌症干细胞（CSC）驱动。阿贝西利显示出治疗GBM的潜力，尽管其除RB磷酸化之外的机制尚未完全了解。本研究表明，阿贝西利通过GSK3β介导的CD44和TCF7L2调节影响EMT途径，从而减少GBM球体形成。阿贝西利治疗显著阻碍了GBM细胞中的球体形成，转录组分析表明EMT途径受到抑制。从机制上讲，阿贝西利通过抑制GSK3β磷酸化，持续降低亲本细胞和球体细胞中CD44和TCF7L2的表达。一种GSK3β药理学抑制剂产生了类似的效果，强化了GSK3β - CD44/TCF7L2轴的存在。此外，原位异种移植证实了体内肿瘤生长和CD44表达的减少。对TCGA和CGGA数据集的分析表明，与不良预后相关的间充质GBM亚型（MES - GBM）表现出EMT基因表达升高。用阿贝西利处理MES样LN229细胞导致GSK3β磷酸化减少以及EMT相关基因表达降低。我们的研究结果突出了阿贝西利一种新的EMT抑制作用，阐明了其针对CSC和治疗MES - GBM的治疗潜力。这项研究为将阿贝西利重新用作侵袭性胶质母细胞瘤的靶向治疗提供了机制见解和依据。
