Santiago, Rhyla; (2025) Understanding the role of dormancy in glioblastoma radioresistance. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glioblastoma is the most common and aggressive type of brain cancer in adults. Although it is treated with combined surgery and chemoradiotherapy, patients inevitably experience tumour recurrence. The efficacy of this treatment is limited partly by the increased radio-resistance of this disease. One source of this radio-resistance may in fact be tumour cell dormancy, a state of reversible cell cycle arrest. Indeed, radiotherapy is thought to preferentially target proliferating tumour cells, which may progress rapidly through the cell cycle with attenuated capacity for DNA repair. The extended presence of radiation-induced DNA damage in these proliferating tumour cells eventually triggers cell death. Thus, dormant cells are thought to survive radiotherapy, yet the mechanisms underpinning this radio-resistance remain unclear. Another layer of complexity arises from the potential heterogeneity of the dormant population in glioblastoma. This tumour is distributed into the cell states resembling that of normal neurodevelopment, it follows that the dormant population may also consist of multiple cell states with potentially heterogenous mechanisms of radio-resistance. Given this context, we sought to first characterise the dormant population in an immunocompetent mouse model of glioblastoma and assess its radiation-response. In fact, we identified a dormant astrocyte-like population that was radioresistant, and interestingly, driven by tumour-derived BMP signalling. We modelled this population in vitro through BMP4/FGF treatment to determine the mechanisms underlying their radio-resistance. To this end, we demonstrated the significance of MMEJ in the DNA Damage repair of this dormant population in vitro. Certainly, we demonstrated that MMEJ inhibition significantly improved the survival benefit of chemoradiotherapy in vivo. Collectively, this work advances our understanding of the radioresistance mechanisms of the dormant tumour cells in glioblastoma and highlights the potential in utilising MMEJ inhibition to target this radio-resistant dormant population.

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