Axonal injury is a targetable driver of glioblastoma progression

Melanie Clements, Wenhao Tang, Zan Florjanic Baronik, Holly Simpson Ragdale, Roger Oria, Dimitrios Volteras, Ian J. White, Gordon Beattie, Imran Uddin, Tchern Lenn, Rachel Lindsay, Sara Castro Devesa, Saketh R. Karamched, Mark F. Lythgoe, Vahid Shahrezaei, Valerie M. Weaver, Ryoichi Sugisawa, Federico Roncaroli, Samuel Marguerat, Ciaran S. Hill () and Simona Parrinello ()
Additional contact information
Melanie Clements: UCL Cancer Institute
Wenhao Tang: Imperial College London
Zan Florjanic Baronik: UCL Cancer Institute
Holly Simpson Ragdale: UCL Cancer Institute
Roger Oria: University of California
Dimitrios Volteras: Imperial College London
Ian J. White: University College London
Gordon Beattie: University College London
Imran Uddin: University College London
Tchern Lenn: University College London
Rachel Lindsay: UCL Cancer Institute
Sara Castro Devesa: UCL Cancer Institute
Saketh R. Karamched: UCL Cancer Institute
Mark F. Lythgoe: University College London
Vahid Shahrezaei: Imperial College London
Valerie M. Weaver: University of California
Ryoichi Sugisawa: Kindai University Faculty of Medicine
Federico Roncaroli: University of Manchester
Samuel Marguerat: University College London
Ciaran S. Hill: UCL Cancer Institute
Simona Parrinello: UCL Cancer Institute

Nature, 2025, vol. 646, issue 8084, 452-461

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09411-2

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