Understanding mechanisms of glioblastoma invasion through manipulation of the tumour microenvironment
Primary Supervisor: Simona Parrinello, UCL
Secondary supervisors: Sam Rodriques, Francis Crick Institute; Ciaran Hill, UCL
Project
Project background and description
Glioblastoma is the commonest intrinsic brain tumour and it is almost universally fatal with a median survival under 16 months. The disease is challenging to treat because of rapid growth and inexorable spread. Factors governing growth, invasion, and recurrence remain poorly understood.
When glioblastoma invades it induces injury in the adjacent brain including axons and white-matter. Wallerian degeneration is an injury-inducible cell-autonomous axon-degeneration pathway whose molecular mechanism has recently been elucidated. We have exciting new data showing that by modulating this pathway we can alter the spread and development of glioblastoma. These results are important because understanding how Wallerian degeneration associated microenvironmental changes govern tumour growth, proliferation and invasion may provide insights into the wide variation in progression and treatment response seen in human glioblastoma. Furthermore, Wallerian degeneration is a pathway that has established pharmacological targets.
Project aims and methodology
The primary aims of this study will be to understand the role of Wallerian degeneration in glioblastoma initiation, to identify the cellular and molecular mechanisms by which manipulating Wallerian degeneration affects tumour behaviour, and to determine the effect of pharmacological manipulation of Wallerian degeneration in combination with existing therapies.
The student will use a range of state-of-the-art methodologies including advanced somatic models (CRISPR/Cas9 piggyBac-mediated transposition technology) to generate glioblastoma with characteristic mutational profiles in immunologically competent mice. This technology will be combined with transgenic mice with altered Wallerian degeneration susceptibility (gene-trap/knockout transgenic models) to explore the Wallerian degeneration/glioblastoma relationship. The student will use these in vivo systems and complementary organotypic brain slice models, to define the cell-cell interactions that underpin growth, proliferation and invasion using a combination of techniques including multiplex immunohistochemistry and spatial transcriptomics. The later will be undertaken using technology such as that developed by one of the supervisors Dr Rodriques (SlideSeq). In collaboration with the Dr Marguerat team, the student will have the opportunity to develop the bioinformatic skills to analyse and apply the transcriptomic data. Invasion will be assessed in model system and fresh patient derived tissue in collaboration with novel hyperspectral imaging technology being developed at the WEISS institute.
Novel small molecule inhibitors of Wallerian degeneration have recently been developed. Combining manipulation of axon degeneration with surgery/radiotherapy we can expect to make significant gains in the treatment response. We have the facilities and experience necessary to undertake testing in multiple models systems including mouse models, patient derived organotypic brain slices, and tumour-derived organoids. Patient relevence and a focus on theraputic translation is assured by strong clinical collaboration and supervision the Neurosurgical department.
In addressing these hypotheses the student will dissect underlying mechanisms that determine glioblastoma growth and invasion and in doing so can fundamentally advance the understanding of glioblastoma behaviour and open new opportunities to treat this disease.
Candidate background
This project would suit highly motivated candidates with a background in molecular biology, genetics and/or neuroscience. A genuine interest in cancer research and diseases of the brain would be advantageous.
Potential Research Placements
- Sam Rodriques, Francis Crick Institute
- Samuel Marguerat, UCL Cancer Institute
- Danail Stoyanov, Wellcome / EPSRC Centre for Interventional and Surgical Sciences (WEISS), UCL
References
- Brooks LJ, Clements MP, Burden, JJ et al. The white matter is a pro-differentiative niche for glioblastoma. 2021. Nat Commun. (12) 2184
- Rodriques SG, Sticklers RR, Goeva A et al. Slide-seq: A Scalable Technology for Measuring Genome-Wide Expression at High Spatial Resolution. 2019. Science. (29) 1463-1467
- Hill CS, Coleman MP, Menon DK. Traumatic Axonal Injury: Mechanisms and Translational Opportunities. 2016. Trends Neurosci. (39) 311-324.
- Clements MP, Byrne E, Camarillo Guerrero LF et al. 2017. The wound microenvironment reprogrammes Schwann cells to invasive mesenchymal-like cells to drive peripheral nerve regeneration. Neuron, (96) 98-114
- Coleman MP and Hoke A. Programmed axon degeneration: from mouse to mechanism to medicine. 2020. Nat Rev Neuro. (21) 183-196