Targeting glioblastoma with a brain-penetrant drug that impairs brain tumor stem cells via NLE1-Notch1 complex.

IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING
Stem Cell Reports Pub Date : 2024-11-12 Epub Date: 2024-10-17 DOI:10.1016/j.stemcr.2024.09.007
Audrey Burban, Ahmad Sharanek, Aldo Hernandez-Corchado, Hamed S Najafabadi, Vahab D Soleimani, Arezu Jahani-Asl
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引用次数: 0

Abstract

Brain tumor stem cells (BTSCs) are a population of self-renewing malignant stem cells that play an important role in glioblastoma tumor hierarchy and contribute to tumor growth, therapeutic resistance, and tumor relapse. Thus, targeting of BTSCs within the bulk of tumors represents a crucial therapeutic strategy. Here, we report that edaravone is a potent drug that impairs BTSCs in glioblastoma. We show that edaravone inhibits the self-renewal and growth of BTSCs harboring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. Global gene expression analysis revealed that edaravone significantly alters BTSC transcriptome and attenuates the expression of a large panel of genes involved in cell cycle progression, stemness, and DNA repair mechanisms. Mechanistically, we discovered that edaravone directly targets Notchless homolog 1 (NLE1) and impairs Notch signaling pathway, alters the expression of stem cell markers, and sensitizes BTSC response to ionizing radiation (IR)-induced cell death. Importantly, we show that edaravone treatment in preclinical models delays glioblastoma tumorigenesis, sensitizes their response to IR, and prolongs the lifespan of animals. Our data suggest that repurposing of edaravone is a promising therapeutic strategy for patients with glioblastoma.

通过 NLE1-Notch1 复合物损害脑肿瘤干细胞的脑穿刺药物靶向胶质母细胞瘤。
脑肿瘤干细胞(BTSCs)是一种自我更新的恶性干细胞群,在胶质母细胞瘤肿瘤分级中发挥着重要作用,并导致肿瘤生长、治疗耐药性和肿瘤复发。因此,靶向肿瘤体积内的BTSCs是一种重要的治疗策略。在这里,我们报告了依达拉奉是一种能损害胶质母细胞瘤中 BTSCs 的强效药物。我们发现,依达拉奉能抑制携带多种致癌突变的BTSC的自我更新和生长,而不影响非致癌神经干细胞。全局基因表达分析表明,依达拉奉能显著改变BTSC转录组,并减弱参与细胞周期进展、干性和DNA修复机制的大量基因的表达。从机理上讲,我们发现依达拉奉直接靶向Notchless同源物1(NLE1),损害了Notch信号通路,改变了干细胞标志物的表达,并使BTSC对电离辐射(IR)诱导的细胞死亡反应敏感。重要的是,我们在临床前模型中发现,依达拉奉治疗可延缓胶质母细胞瘤的肿瘤发生,使其对IR反应敏感,并延长动物的寿命。我们的数据表明,依达拉奉的再利用对于胶质母细胞瘤患者来说是一种很有前景的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Stem Cell Reports
Stem Cell Reports CELL & TISSUE ENGINEERING-CELL BIOLOGY
CiteScore
10.50
自引率
1.70%
发文量
200
审稿时长
28 weeks
期刊介绍: Stem Cell Reports publishes high-quality, peer-reviewed research presenting conceptual or practical advances across the breadth of stem cell research and its applications to medicine. Our particular focus on shorter, single-point articles, timely publication, strong editorial decision-making and scientific input by leaders in the field and a "scoop protection" mechanism are reasons to submit your best papers.
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