Decoding the Mechanisms Underlying Cell State Plasticity in Glioblastoma
Primary Supervisor: Dr Lucy Brooks
Second Supervisor: Professor Geoff Higgins
Project Overview
Glioblastoma is the most common intrinsic malignant primary brain tumour in adults, with an average survival of 14-16 months. This dismal prognosis can be attributed to the pronounced resistance to existing therapeutic interventions, which involves surgery, chemotherapy, and radiation. Consequently, there is an urgent need to understand and target resistance mechanisms in this disease. Glioblastoma exhibits remarkable cellular plasticity, enabling tumour cells to transition between distinct states. Our work and that of others has shown that these states are not random but mirror neurodevelopmental and injury-response programmes that tumour cells can hijack. Each state is linked to specific biological behaviours, microenvironmental interactions, and therapy sensitivities—some states are highly susceptible to treatment, whereas others are markedly resistant. Deciphering and controlling these transitions could be pivotal in overcoming therapeutic resistance. This PhD project will investigate the molecular and microenvironmental mechanisms underpinning glioblastoma cell state plasticity. It will explore how intrinsic and extrinsic cues drive shifts into therapy-resistant states, with the aim of identifying regulatory nodes that can be therapeutically targeted to constrain plasticity and bias tumours toward more treatable states. The research will employ cutting-edge approaches, including patient-derived organoid and co-culture systems to model tumour–microenvironment interactions, CRISPR gene editing to test candidate genes, and high-dimensional single-cell analyses (e.g., mass cytometry) to define state-specific phenotypes. By integrating high-fidelity experimental models with high-resolution molecular profiling, this work will generate new insights into glioblastoma cell state dynamics and how they can be disrupted to prevent recurrence. This project offers the opportunity to address a fundamental challenge in brain cancer biology, while building advanced wet-lab expertise alongside bioinformatics and integrative analysis skills.
Training Opportunities
The student will gain extensive training in cancer biology, molecular techniques, and high-dimensional data analysis. Wet-lab skills will include patient-derived organoid culture, co-culture modelling of tumour–microenvironment interactions, CRISPR-Cas9 genome editing, and single-cell technologies such as mass cytometry. The student will also develop expertise in advanced microscopy and quantitative imaging. Bioinformatics training will encompass data preprocessing, statistical analysis, and visualisation of single-cell and bulk molecular datasets. The project will also provide experience in experimental design, troubleshooting, and critical data interpretation, supported by regular supervision and feedback. The student will actively engage in seminars and journal clubs, present at internal meetings, and have opportunities to share their findings at national and international conferences, strengthening scientific communication and professional skills. They will also be encouraged to attend specialist skills workshops throughout the PhD to broaden their expertise.
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.