通过WNT-WWC1-YAP轴抑制胶质瘤干细胞中的Gsk3β实现合成致死性。

Synthetic lethality through Gsk3β inhibition in glioma stem cells via the WNT-WWC1-YAP axis.

作者信息

Ren Fangfang, Yi Yulan, Lu Ting, Liu Xinze, Cui Gang, Huang Song, Parada Luis F, Chen Jian

机构信息

National Institute of Biological Sciences, Beijing, China.

Institute of Functional Nano and Soft Materials (FUNSOM) & Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, China.

出版信息

Oncogene. 2025 Apr 23. doi: 10.1038/s41388-025-03418-9.

DOI:10.1038/s41388-025-03418-9

PMID:40269262

Abstract

Glioblastoma (GBM) is an aggressive brain tumor driven by glioma stem cells (GSCs), which contribute to tumor growth and therapeutic resistance. This study investigates the effects of Gsk3β inhibition on GSC viability, focusing on the role of the canonical WNT signaling pathway. We found that Gsk3β inhibition activates the WNT pathway, leading to upregulation of Wwc1, which downregulates Yap via Lats1 phosphorylation. This reduces GSC proliferation, self-renewal, and enhances chemosensitivity. Analysis of clinical datasets revealed that WNT pathway activation correlates with improved prognosis in proneural gliomas, particularly in IDH1-mutated tumors. Our findings suggest that targeting the WNT-WWC1-YAP axis, particularly through Gsk3β inhibition, could induce synthetic lethality in GSCs and provide a promising therapeutic strategy for gliomas. These results highlight the potential of exploiting WNT-induced synthetic lethality as a novel approach for glioma treatment.

摘要

胶质母细胞瘤（GBM）是一种由胶质瘤干细胞（GSCs）驱动的侵袭性脑肿瘤，胶质瘤干细胞会促进肿瘤生长并导致治疗耐药。本研究调查了糖原合成酶激酶3β（Gsk3β）抑制对胶质瘤干细胞活力的影响，重点关注经典WNT信号通路的作用。我们发现，抑制Gsk3β会激活WNT通路，导致Wwc1上调，而Wwc1会通过磷酸化Lats1来下调Yes相关蛋白（Yap）。这会减少胶质瘤干细胞的增殖和自我更新，并增强化学敏感性。对临床数据集的分析表明，WNT通路激活与神经干细胞型胶质瘤患者，尤其是异柠檬酸脱氢酶1（IDH1）突变肿瘤患者的预后改善相关。我们的研究结果表明，靶向WNT-WWC1-Yap轴，特别是通过抑制Gsk3β，可能会在胶质瘤干细胞中诱导合成致死，并为胶质瘤提供一种有前景的治疗策略。这些结果凸显了利用WNT诱导的合成致死作为胶质瘤治疗新方法的潜力。