FGFR3 regulation of quiescence and therapeutic vulnerability in glioblastoma stem cells

Begum, Ayesha 2026. FGFR3 regulation of quiescence and therapeutic vulnerability in glioblastoma stem cells. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

The treatment of Glioblastoma (GBM), an aggressive primary brain tumour, is often a process of clearing the visible tumour while residual cells persist, leading to the near-universal recurrence that defines this disease. These cells are glioma stem cells (GSCs), which possess the ability to enter a reversible, actively maintained quiescent state to survive the effects of conventional chemotherapy. Although quiescent GSCs exit the cell cycle, the molecular mechanisms that stabilise this state, or the vulnerabilities they might expose remain incompletely understood. This thesis investigates the signalling networks that govern GSC quiescence, focusing specifically on the role of fibroblast growth factor 3 (FGFR3). Using a bone morphogenetic protein 4 (BMP4)-induced model of reversible quiescence, I observed a shift in receptor signalling dynamics as GSCs enter a therapy-tolerant state, characterised by reduced FGFR1 activity and enrichment of FGFR3-positive cells. Functional interrogation demonstrated that FGFR3 is necessary to maintain cell-cycle suppression in this context. However, the inability of FGFR3 to induce this state alone, indicates that quiescence is not controlled by a single master regulator, but instead emerges from a distributed and interconnected signalling network. To define this signalling architecture, unbiased kinome profiling was performed across proliferative, BMP4-induced quiescent and FGFR1+ve, FGFR3+ve and FGFR1/3-ve, -sorted GSC populations. Profiling of both protein tyrosine kinases (PTKs) and serine/threonine kinases (STKs) highlighted distinct patterns of signalling suppression and retention. Quiescent GSCs showed suppression of cell cycle-associated STK activity, including kinases linked to CDK and mitotic signalling, alongside attenuation of mitogenic PTK signalling and selective retention of receptor tyrosine kinase (RTK) inputs. These findings indicate that quiescent states arise through rebalancing of a shared signalling network rather than establishment of a distinct programme, with FGFR3 biasing this network towards quiescence. Functional testing of a candidate kinase regulator within this network demonstrates how we can leverage kinome profiling to identify new ways to interrogate signalling nodes influencing quiescence-associated phenotypes. Ultimately, this work frames FGFR3-associated quiescence as a regulated state, providing a new framework for targeting the quiescent populations that have made GBM a therapy-refractory challenge.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	25 June 2026
Last Modified:	25 Jun 2026 11:55
URI:	https://orca.cardiff.ac.uk/id/eprint/187740

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