Axon Damage Found To Accelerate Glioblastoma Progression

A study published in Nature has shown that early glioblastomas in mice trigger a brain injury response that accelerates tumor growth. Researchers found that when nerve cells were damaged, the brain initiated a cleanup process that unexpectedly promoted the tumor’s development.

“Our study reveals a new way that we could potentially delay or even prevent glioblastomas from progressing to a more advanced state."

Professor Simona Parrinello.

Glioblastomas are aggressive brain tumors that develop from mutated brain cells. In this study, scientists at the University College London Cancer Institute used genetically engineered mice to observe how glioblastomas evolve in their earliest stages. Early tumors damaged axons – the long projections of nerve cells – especially in white matter regions, initiating a process called Wallerian degeneration.

Wallerian degeneration is the breakdown of axons following injury. This process is mediated by a protein called SARM1, which destroys the axon’s energy source, NAD⁺. The researchers observed that this degeneration caused inflammation, which correlated with a shift in tumor behavior, making them more aggressive.

Disabling SARM1 slowed tumor growth

When mice were genetically modified so that their SARM1 protein was inactive, damaged axons remained intact for longer. These mice developed less aggressive tumors, lived longer and retained more normal brain function than mice in which SARM1 remained active. In contrast, mice with a normal injury response experienced faster tumor progression and neurological decline.

To further examine the link, the team induced axonal damage in healthy mice. This led to more rapid tumor growth, reinforcing the idea that the brain’s injury response supports tumor expansion.

Potential for early intervention

SARM1 inhibitors are currently under investigation in early-phase clinical trials for neurodegenerative conditions such as traumatic brain injury and motor neuron disease. The authors of this study suggest that these inhibitors may also have potential in glioblastoma, although further preclinical work is needed before testing in human cancer patients.

Current treatments for glioblastoma typically involve a combination of surgery, radiotherapy and chemotherapy. However, outcomes remain poor. In the UK, about 3,000 people are diagnosed with glioblastoma each year, and average survival is 12–18 months from diagnosis.

"Current therapies do not work well for glioblastoma, which is extremely difficult to treat, in part because it is typically diagnosed when it is already very advanced. These tumours are also linked to debilitating neurological symptoms. Blocking the brain damage triggered by tumour growth could be beneficial in two ways - by slowing the progression of the cancer and by reducing disability."

Professor Simona Parrinello

The mouse model used in this study allowed researchers to observe glioblastomas at an earlier point than is typically possible in humans, where early-stage tumors are rarely detected.

The research supports further investigation into how cancer interacts with the nervous system, particularly the role of inflammation and injury-related signals in promoting tumor development. These findings may inform future therapeutic strategies aimed at slowing disease progression by modulating the brain’s response to injury.

“The next step is to see if SARM1 inhibitors already being trialled for other neurodegenerative diseases could also be used to treat this aggressive form of brain cancer. However, we need to do more work in the lab before these inhibitors can be tried in patients with glioblastoma.”

Professor Simona Parrinello.

Reference: Clements M, Tang W, Florjanic Baronik Z, et al. Axonal injury is a targetable driver of glioblastoma progression. Nature. 2025. doi: 10.1038/s41586-025-09411-2

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