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A Human Glioblastoma Organotypic Slice Culture Model for Study of Tumor Cell Migration and Patient-specific Effects of Anti-Invasive Drugs
Published on: July 20, 2017
Axonal injury is a targetable driver of glioblastoma progression
Melanie Clements1, Wenhao Tang2, Zan Florjanic Baronik1
1Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, London, UK.
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.
Insights
Axonal injury drives glioblastoma (GBM) progression by triggering inflammation and tumor growth. Inhibiting SARM1, which mediates axonal death, blocks this process, offering a new strategy for GBM interception.
Area of Science:
- Neuroscience
- Oncology
- Cell Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor prognosis.
- Early GBM development mechanisms are poorly understood, hindering effective treatment.
- Current research focuses on advanced disease, neglecting earlier, more treatable stages.
Purpose of the Study:
- To investigate the role of axonal injury in early glioblastoma development.
- To elucidate the mechanisms by which axonal injury promotes gliomagenesis.
- To explore SARM1 inhibition as a therapeutic strategy for GBM.
Main Methods:
- Identifying axonal injury as a driver of GBM progression in white matter.
- Investigating the link between axonal injury, Wallerian degeneration, and neuroinflammation.
- Assessing the impact of SARM1 inactivation on tumor development and survival in mouse models.
Main Results:
- Early GBM cells induce axonal injury in white matter, promoting gliomagenesis.
- Axonal injury triggers Wallerian degeneration, increasing neuroinflammation and tumor proliferation.
- SARM1 inactivation disrupts this pro-tumorigenic loop, reducing tumor aggressiveness and improving survival.
Conclusions:
- Targeting tumor-induced axonal injury and neuroinflammation is a potential strategy for GBM interception.
- Inhibiting SARM1 may offer a novel therapeutic approach to control GBM progression.
- Understanding early GBM development is crucial for developing effective treatment and control strategies.
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