Axonal injury is a targetable driver of glioblastoma progression

• 成果类型: Article
• 署名作者: 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
• 署名单位: University of London; University College London; Imperial College London; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of London; University College London; University of London; University College London; University of London; University College London; University of London; University College London; University of London; University College London; University of London; University College London; University of California System; University of California San Francisco; Kindai University (Kinki University); University of Manchester; University College London Hospitals NHS Foundation Trust; University of London; National Hospital for Neurology & Neurosurgery; University College London; UCL Medical School
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09411-2
• 发表日期: 2025-10-09
• 关键词: cell; sarm1; activation; PROGRAMS; MODEL; idh1

摘要

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.