Shen, Xinyi; (2025) The role of transcription factor dynamics in cell fate regulation in high grade gliomas. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Gliomas comprise diverse cancer cell populations that transcriptionally resemble different normal brain progenitor and differentiated glial cells, which exhibit varying sensitivities to therapies. Cancer cells can dynamically transition between these transcriptional states, and therapy also induces cell state transitions. Understanding how these transitions are regulated could be exploited to guide cells into treatment-sensitive or less proliferative states to increase patient survival. However, the molecular mechanisms governing the differential sensitivities and plasticity of these cell states are poorly understood. Therefore, I investigated the role of transcription factor dynamics in regulating glioma cell fate decisions through bioinformatics and computational modelling approaches applied to single-cell transcriptomics data from glioblastoma and diffuse midline glioma patient tumours and mouse models. In a mouse model of glioblastoma treated with radiotherapy, I identified distinct proliferative and differentiated populations of resistant tumour cells and found that cell fate may be influenced by radiation-induced hypertranscription. Using diffuse midline glioma patient samples, I inferred that cells associated with worse response to radiotherapy were quiescent and maintained low reactive oxygen species through high activity of the transcription factor NRF2. To study transcription factor dynamics, I benchmarked the performance of algorithms that infer oscillatory gene expression from single time point single cell measurements, establishing Cyclum and scPrisma as the best methods in different contexts. Applying these methods to normal brain development data, I revealed Ascl1 oscillations specifically in neural progenitors, with region-specific regulatory mechanisms potentially involving Hes1 and Dll1. Significant coupling of PRC2 to the cell cycle was found in diffuse midline glioma studies, with clinical implications for radiotherapy optimisation. It was also shown that oscillatory expression of ASCL1 and OLIG2 in gliomas may maintain the undifferentiated state of neural progenitor cells and promote tumour cell proliferation by affecting cellular plasticity. These findings suggest potential therapeutic strategies targeting transcription factor dynamics.

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