Florjanic Baronik, Zan;
(2025)
The Role of Axonal Injury in Glioblastoma Progression.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Glioblastoma (GBM) is the most common and most lethal type of primary brain cancer in adults, characterised by poor therapeutic response and significant impact on patient quality of life. While tumour–neuron interactions are increasingly recognised as key drivers of gliomagenesis, the role of axonal injury in shaping tumour progression remains unclear. Importantly, most insights into GBM biology are derived from late-stage disease, whereas the early phases, where critical determinants of progression likely emerge, remain poorly understood. This thesis addresses this gap by investigating early gliomagenesis using a somatic CRISPR-based mouse model of GBM. A spatiotemporal analysis revealed that early-stage tumours preferentially infiltrate white matter tracts, where they induce progressive axonal degeneration and local neuroinflammation. Mechanistically, tumour-induced axonal injury was shown to occur via the Wallerian degeneration pathway, dependent on SARM1. Genetic deletion of Sarm1 preserved axonal integrity and altered tumour phenotype. Tumours which formed in Sarm1–/– mice exhibited a more diffuse architecture, reduced mesenchymal cell states, and a less inflamed tumour microenvironment. These changes translated into prolonged survival and preserved neurological function. Collectively, these findings position axonal degeneration as a key driver of GBM progression, and highlight the tractability and importance of studying early disease as a window into actionable drivers of malignancy. SARM1 may represent a promising therapeutic target for both suppressing tumour progression and preserving neurological function in GBM.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The Role of Axonal Injury in Glioblastoma Progression |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10215711 |
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