伦敦大学学院癌症研究所Simona Parrinello小组取得一项新突破。他们的最新研究提出了轴突损伤是胶质母细胞瘤进展的可靶向驱动因素。2025年8月20日出版的《自然》杂志发表了这项成果。

在这里，该课题组人员确定轴突损伤是GBM进展的关键驱动因素，该课题组人员发现早期肿瘤细胞在该区域优先扩张在白质中诱导。从机制上讲，轴突损伤通过触发沃勒氏变性促进胶质瘤的形成，这是轴突死亡的一种可靶向的活性程序，研究人员发现这增加了神经炎症和肿瘤的增殖。SARM1是对损伤反应中激活的关键酶，介导了沃勒氏变性，其失活足以打破这种促进肿瘤的前馈循环，导致小鼠晚期肿瘤的发展和生存期的延长。它们靶向肿瘤诱导的损伤微环境可能抑制从潜伏到晚期疾病的进展，从而为GBM的拦截和控制提供了一种潜在的策略。

据介绍，胶质母细胞瘤（GBM）是一种侵袭性强且具有高度治疗耐药性的脑肿瘤。尽管已经对晚期疾病进行了深入研究，但支持早期（可能更容易处理的）GBM发展阶段的机制仍然知之甚少。

附：英文原文

Title: Axonal injury is a targetable driver of glioblastoma progression

Author: Clements, Melanie, Tang, Wenhao, Florjanic Baronik, Zan, Simpson Ragdale, Holly, Oria, Roger, Volteras, Dimitrios, White, Ian J., Beattie, Gordon, Uddin, Imran, Lenn, Tchern, Lindsay, Rachel, Castro Devesa, Sara, Karamched, Saketh R., Lythgoe, Mark F., Shahrezaei, Vahid, Weaver, Valerie M., Sugisawa, Ryoichi, Roncaroli, Federico, Marguerat, Samuel, Hill, Ciaran S., Parrinello, Simona

Issue&Volume: 2025-08-20

Abstract: Glioblastoma (GBM) is an aggressive and highly therapy-resistant brain tumour1,2. Although advanced disease has been intensely investigated, the mechanisms that underpin the earlier, likely more tractable, stages of GBM development remain poorly understood. Here we identify axonal injury as a key driver of GBM progression, which we find is induced in white matter by early tumour cells preferentially expanding in this region. Mechanistically, axonal injury promotes gliomagenesis by triggering Wallerian degeneration, a targetable active programme of axonal death3, which we show increases neuroinflammation and tumour proliferation. Inactivation of SARM1, the key enzyme activated in response to injury that mediates Wallerian degeneration4, was sufficient to break this tumour-promoting feedforward loop, leading to the development of less advanced terminal tumours and prolonged survival in mice. Thus, targeting the tumour-induced injury microenvironment may supress progression from latent to advanced disease, thereby providing a potential strategy for GBM interception and control.

DOI: 10.1038/s41586-025-09411-2

Source: https://www.nature.com/articles/s41586-025-09411-2