Identifying the injury signals that drive early glioblastoma growth
Primary supervisor: Simona Parrinello, UCL
Secondary supervisor: Samuel Marguerat, UCL
Project
Glioblastoma (GBM) is a devastating disease for which current treatments remain inadequate and median patient survival at less than 18 months. The pervasive cellular and molecular heterogeneity of late stage GBM, coupled with its highly infiltrative nature, are major causes of treatment resistance, suggesting that strategies aimed at earlier intervention and/or prevention may be more effective at improving patient outcome.
Both mouse models and longitudinal MRI imaging in patients indicate that GBM often progresses from a stage of diffuse slow proliferative disease to an explosive growth stage that rapidly leads to symptomatic disease. This provides a window of opportunity for early intervention as identification of the mechanisms that underlie this switch might provide actionable targets for preventing the disease or slowing down its progression.
Over the past few years, our work has uncovered a key role for injury programmes in GBM, including a central role for neuronal degeneration and demyelination. Preliminary data further suggest that the switch to explosive growth may be driven by normal glia that become inflamed, as a result of early tumour cells injuring the surrounding normal brain tissue. The aim of this project is to characterise the nature of this glial population and identify the injury signals by which they support tumourigenesis.
The project will build on novel immunocompetent mouse models of GBM developed in our laboratory and use a variety of state-of-the-art technologies, including spatial and scRNA-transcriptomics and in vivo gain and loss of function experiments. Results from the mouse models will be validated in organotypic cultures of human patient material. The project will provide fundamental insights into early GBM biology and has the potential to identify novel strategies for early intervention.
References
- Brooks et al., Nature Comms 2021
- Simpson Ragdale et al., Curr Biol 2023
- Richards et al., Nature Cancer 2022
- Stensjøen et al., Clin. Neurol and Neuros, 2018
- Yeo et al., Nature Immunology 2022