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Dr Lucy Brooks
Glioblastoma is a highly aggressive brain cancer and the leading cause of cancer-related death in people under 40. Despite intensive treatment involving surgery, chemotherapy, and radiotherapy, resistance to treatment remains a major challenge and around 75% of patients die within one year of diagnosis.
New research is investigating how polyploid tumour cells contribute to tumour biology. These cells contain multiple sets of chromosomes instead of the normal two and are often induced when stressors, such as chemotherapy and radiotherapy, disrupt normal cell division. Their increased genetic content makes them highly adaptable, enabling rapid evolution to evade immune surveillance and drug therapies.
Earlier work by Dr Brooks and her team found that radiotherapy dramatically increases whole genome doubling in glioblastoma cells, leading to the formation of polyploid cells through mitotic failure. Across multiple laboratory models, levels of polyploidy rose from fewer than 4% of cells before treatment to between 20% and 50% after radiation, in a dose-dependent manner.
As these cells persist and produce proliferative, malignant progeny, it is thought they may form a durable, treatment-resistant subpopulation that contributes to long-term tumour maintenance and disease recurrence. While whole genome doubling has been linked to tumour progression and poor prognosis in other cancers, little is currently known about the role of polyploidy in glioblastoma.
With funding from Brain Research UK, Dr Brooks will investigate how radiation-induced polyploid cells survive and whether these mechanisms can be exploited therapeutically to improve treatment response and reduce recurrence.
How do radiation-induced polyploid cells survive?
The first stage of the project will focus on identifying the genes that enable polyploid cells to survive following radiation. In a whole genome CRISPR screen of irradiated glioblastoma cells, the team identified numerous genetic dependencies linked to replication stress tolerance, mitotic fidelity, chromatin regulation and stemness. Researchers will now prioritise around 50 genes for further study, focusing on those that specifically affect polyploid cells and may be targetable with drugs. These targets will then be validated in glioblastoma-derived cell lines to assess how disrupting them affects treatment response at the single-cell level.
What mechanisms underpin survival?
The second phase of the research will explore the biological mechanisms that underpin the genetic vulnerabilities of polyploid cells. Using live cell imaging, the team will monitor how these cells progress through the cell cycle and determine how disrupting key survival pathways triggers cell death. Irradiated cells will be tracked continuously for several days to map the effects of modifying individual genes in real time.
Can these mechanisms be targeted?
Finally, the researchers will investigate whether these vulnerabilities can be therapeutically targeted in patient-derived glioblastoma organoids, assessing how inhibiting them with small molecules impacts treatment response.
The project brings together expertise spanning laboratory, computational and clinical research. Dr Brooks will work closely with Professor Puneet Plaha, consultant neurosurgeon at Oxford University Hospitals, whose expertise in glioblastoma and access to patient-derived tumour samples will help ensure that discoveries made in the laboratory are developed with clinical relevance in mind. The wider team includes Dr Jamie Dean (UCL), an expert in computational radiation biology and live-cell imaging, and Dr Xiao Qin (University of Oxford), who specialises in high-throughput single-cell analysis, providing complementary expertise to investigate the mechanisms that underpin treatment resistance in glioblastoma.
Dr Brooks said:
“Radiotherapy causes a dramatic increase in polyploid tumour cells, and these cells may represent a hidden driver of glioblastoma recurrence. With this funding, we hope to understand how these cells survive and whether they can be specifically targeted to improve treatment response and reduce the chances of tumours returning. Resistance and recurrence remain some of the biggest challenges in glioblastoma, so identifying new ways to tackle these problems is a major research priority to improve outcomes for patients.”
Radiation-induced polyploidy in glioblastoma may have significant consequences on patient outcomes by forming a persistent reservoir of treatment-resistant cancer cells. Through this work, Dr Brooks and her team hope to expose weaknesses that could be targeted to improve treatment outcomes and lower rates of recurrence.