Investigating neuronal injury programmes as a determinant of glioblastoma initiation

Primary supervisor: Ciaran Hill, UCL

Secondary supervisor: Andrea Serio, Francis Crick Institute

Project

Glioblastoma is an incurable form of brain cancer that is universally fatal. It is the commonest intrinsic brain tumour and median survival is less than 16 months even with our most efficacious treatment protocols. The disease is challenging to treat because of rapid growth and inexorable spread. Factors governing growth, invasion, and recurrence are poorly understood but are critical to confronting this devastating disease.

At the time glioblastoma is diagnosed it is typically advanced, highly therapy-resistant and inevitably incurable. Improving outcomes in this devastating disease will require earlier detection and intervention. However, limited understanding of glioblastoma initiation mechanisms has hampered progress towards this goal.

Key findings

We have recently discovered that injury programmes play a key role in glioblastoma initiation. Our data shows that as a glioblastoma begins to grow and spreads it induces an injury in the affected brain including the axons and the associated white-matter. Sarm1-dependent Programmed axon death (also known as Wallerian degeneration) is a form of cell-autonomous, modifiable, axon-degeneration pathway implicated in several neurological diseases. Remarkably, we found that by modulating this pathway we can suppress glioblastoma initiation, whilst ameliorating the motor neurological deficits, and extending survival, providing a potential novel therapeutic strategy to converting glioblastoma into a longer-term, more manageable condition.

Aims of this project

Building on our recent findings, the student will focus on understanding the underlying mechanisms of how the tumour cells can injure axons. There are several ways this may occur including direct physical injury (such as compression or stretch), interruption of axonal transport, or secretion of soluble factors. There may also be a role for indirect effects through other microenironmental cells such as microglia or astrocytes. Resolving this question will involve a variety of techniques available in the supervisors laboratory including developing neuronal culture devices with complex bio-engineered designs to allow representative direct analysis of cell-to-cell interactions at a subcompartmental level. These systems will allow micro-force analysis and live cell imaging. The neuronal systems used to answer these questions would include primary neuronal cultures, iPSc, co-cultures, and tumour-bearing organotypic systems developed in the host laboratory.

These techniques will be complemented by additional multi-modality approaches including advanced genetically engineered (CRISPR-Cas 9 piggybac/piggybase) mouse models, singe cell/spatial transcriptomics and multiplex flow cytometry.

This project will fundamentally advance the understanding of glioblastoma behaviour and open up new opportunities to treat this disease. In addition the student will gain vital training in scientific principles and core molecular biological/genetic techniques in a supportive and collaborative environment.

Candidate background

This project would suit highly-motivated candidates with a background in molecular biology, genetics, immunology, and/or neuroscience. A genuine interest in cancer research would be advantageous.

Potential Research Placements

1. Simona Parrinello, Cancer Institute, UCL
2. Andrea Serio, Francis Crick Institute
3. Samuel Marguerat, Cancer Institute, UCL

References

1. McKinnon, C., Nandhabalan, M., Murray, S. A. & Plaha, P. Glioblastoma: clinical presentation, diagnosis, and management. Bmj 374, n1560 (2021).
2. Brooks LJ, Clements MP, Burden, JJ et al. The white matter is a pro-differentiative niche for glioblastoma. 2021. Nat Commun. (12) 2184
3. Hill CS, Coleman MP, Menon DK. Traumatic Axonal Injury: Mechanisms and Translational Opportunities. 2016. Trends Neurosci. (39) 311-324.
4. Coleman MP and Hoke A. Programmed axon degneration: from mouse to mechanism to medicine. 2020. Nat Rev Neuro. (21) 183-196
5. Hagemann C, Bailey MCD, Carraro E, Stankevich KS, Lionello VM, Khokhar N, Suklai P, Moreno-Gonzalez C, O’Toole K, Konstantinou G, Dix CL, Joshi S, Giagnorio E, Bergholt MS, Spicer CD, Imbert A, Tedesco FS, Serio A. Low-cost, versatile, and highly reproducible microfabrication pipeline to generate 3D-printed customised cell culture devices with complex designs. PLoS Biol. 2024 Mar 13;22(3):e3002503. doi: 10.1371/journal.pbio.3002503. PMID: 38478490; PMCID: PMC10936828.