Functional genetic dissection of treatment-resistance in glioblastoma using live-cell imaging

Primary Supervisor: Dr Lucy Brooks

Project Overview

Glioblastoma is one of the most aggressive and deadly cancers, with an average survival of 14-16 months. Standard treatments, including surgery, radiation and chemotherapy, are rarely curative, in part because tumour cells are highly adaptable. We have identified a population of polyploid cells, which arise following radiation due to mitotic failure, resulting in whole genome duplication. These cells persist for long periods and retain the ability to seed new growth, suggesting they play a role in recurrence. However, the mechanisms that allow polyploid cells to survive remain unclear.   Polyploidy represents a fundamental disruption of cell cycle control, and the survival of these cells likely depends on phase-specific adaptive mechanisms. This project will investigate how polyploid glioblastoma cells persist after radiation by building on results from our recent genetic screen, which highlighted candidate genes essential for polyploid cell survival. We will explore how disrupting these genes can alter cellular processes and trigger cell death.   Because cell-cycle-related processes are heterogeneous and unfold over time, we will use live-cell imaging of patient-derived cells engineered to express fluorescent reporters of cell cycle and DNA damage. This will enable real-time single-cell tracking of DNA replication, damage responses and cell cycle transitions. In doing so, we will determine how genes thought to be essential for polyploid survival contribute to their persistence, and how their disruption can create vulnerabilities during cell cycle progression that limit the capacity of these cells to adapt and survive.   This work will pinpoint weak points in polyploid glioblastoma cells that could be exploited therapeutically. At the same time, the project will establish a scalable imaging platform for studying tumour cell behaviour at single-cell resolution, providing a powerful resource for future research. Together, these advances will generate mechanistic insights to inform new treatment strategies aimed at preventing recurrence in this devastating disease.

References 

Brooks, L.J., Ragdale, H.S., Hill, C.S., Clements, M. and Parrinello, S., 2022. Injury programs shape glioblastoma. Trends in Neurosciences, 45(11), pp.865-876.

https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(22)00163-1