UCL-Edinburgh CRUK Glioma Brain Tumour Centre of Excellence PhD Studentship

Mapping alterations in neuronal networks in response to glioblastoma induced neurodegeneration

• Application deadline: 07 July 2025
• Project start: 01 October 2025

Supervisors

Funding and duration

CRUK, funding for 4 years (full-time):

• A non-taxable annual stipend of £23,000 per annum (current CRUK London rate)
• Tuition fees for UK / Home status only.

About the Project

We are seeking a highly motivated PhD student to join the Applied Brain Cancer Biology Laboratory, led by Dr Ciaran Hill at the UCL Cancer Institute. This lab operates as an integrated subgroup within the broader research environment of the Samantha Dickson Brain Cancer Unit and the CRUK Glioma Brain Tumour Centre of Excellence led by Professor Simona Parrinello.

Glioblastoma is the most common primary brain cancer in adults, and it is universally fatal. Despite intensive treatment, median survival typically remains less than 15 months. Its rapid growth, diffuse infiltration, and resistance to therapy make it difficult to treat. Critically, the biological processes underlying glioblastoma initiation, invasion, and recurrence remain poorly understood - limiting our ability to detect and intervene early in disease progression.

The project will leverage advanced somatic CRISPR/Cas9-based mouse models developed at the CRUK Glioma Brain Tumour Centre of Excellence that offer a unique window into the early stages of glioblastoma. Using these models, we have discovered that programs of brain injury play a central role in glioblastoma initiation and progression. Specifically, as glioblastoma expands, it induces physical damage to the surrounding brain tissue resulting in axonal loss via a modifiable, cell-autonomous process also known as Wallerian degeneration. Strikingly, we have found that modulating this pathway improves both disease course and neurological function and extends survival in preclinical models.

This PhD project will explore the bidirectional interaction between glioblastoma cells and the neuronal circuitry they disrupt. We aim to uncover how glioblastoma-induced axonal degeneration affects local and global neural network function, and conversely, how neural activity and connectivity influence tumour behaviour. By characterising these reciprocal interactions at cellular and systems levels, the project will seek to reveal new mechanisms underlying tumour progression and neurological decline - and identify potential intervention points to preserve brain function and delay disease progression.

Aims of this project

Building on recent discoveries in our laboratory, and the evolving field of cancer neuroscience,  the PhD candidate will address fundamental questions at the interface of cancer biology, neuroscience, and neurodegeneration. The overarching goal is to dissect the impact of glioblastoma on neuronal function and brain network connectivity across disease progression, and to identify potential mechanisms by which neuronal activity may modulate tumour growth.

1. Determine the effect of tumour-driven neurodegeneration at a single-cell level

We will map functional alterations in neurons exposed to glioblastoma cells across different stages of tumour development, including early initiation, using high-resolution neurophysiological techniques. This includes whole-cell patch-clamp electrophysiology and calcium imaging in acute and organotypic brain slices. The student will assess how tumour proximity, progression stage, and associated injury responses influence intrinsic neuronal properties (e.g., membrane potential, excitability) and synaptic function across defined neuronal subtypes.

2. Establish neuro-electrical changes in multiple brain regions throughout glioblastoma development

Using chronic implantation of Neuropixels probes in somatic glioblastoma mouse models, the student will record high-density, multi-site single-unit and local field potential activity across the tumour core, invasive margins, and non-infiltrated distal regions. These recordings will allow us to map the spatiotemporal evolution of circuit dysfunction and correlate electrophysiological changes with structural degeneration, tumour burden, and behavioural outcomes. The aim also includes identifying specific neuro-electrical signatures associated with early glioblastoma-induced neuronal stress.

3. Determine how preserving Wallerian degeneration-injured neurons influences brain network function, tumour progression, and early neuronal stress signatures

By combining somatic glioblastoma models with Sarm1⁻/⁻ mice, the student will investigate how inhibiting Wallerian degeneration alters tumour–neuron interactions. In vitro slice cultures and in vivo Neuropixels recordings and calcium imaging will be used to determine whether preserved axons and neurons maintain functional integration or become silent/maladaptive. The project will assess whether neurodegeneration is necessary for glioblastoma to exploit neuronal activity and whether suppressing it influences tumour progression. This system also provides a platform to identify early neuronal stress signatures and circuit-level biomarkers relevant to glioblastoma detection and therapy.

Opportunities

The student will be trained in and have access to a multidisciplinary suite of methods across the laboratories of Dr Hill, Professor Parrinello and collaborators, including:

• Somatic CRISPR/Cas9 mouse models of glioblastoma for inducible tumour initiation.
• In vivo and ex vivo electrophysiology, including patch-clamp recordings, field potential measurements, and Neuropixels-based multi-region recordings.
• Calcium imaging using genetically encoded indicators (such as GCaMP) in slice cultures and, if appropriate, in live animals.
• High-resolution imaging (including as confocal, multiphoton, and light-sheet microscopy) to visualise neurodegeneration and tumour progression
• Organotypic brain slice co-cultures, allowing direct study of tumour-neuron interactions in a semi-intact circuit.
• Single-cell and spatial transcriptomics to define molecular signatures of neuron-tumour interactions and correlate neurophysiological findings with gene expression profiles such as identification of neuronal stress phenotypes.
• Advanced computational analysis, including spike-sorting algorithms, dimensionality reduction, and network connectivity metrics, to interpret large-scale neuronal datasets.

The candidate will gain broad, in-depth training in scientific inquiry, experimental design, and state-of-the-art molecular, cellular, and computational techniques within a dynamic and collaborative research environment.

Potential Impact

This project aims to redefine our understanding of glioblastoma not simply as a malignant growth but as a dynamic perturbation of brain circuitry. By elucidating the interplay between tumour cells and injured neurons, we hope to uncover new biomarkers for early detection and new strategies for neuroprotective or activity-targeted therapy - offering hope for improved patient outcomes in a currently incurable disease.

References

• McKinnon et al. Glioblastoma: clinical presentation, diagnosis, and management. BMJ. 2021.
• C. Hill et al. Traumatic Axonal Injury: Mechanisms and Translational Opportunities. Trends Neurosci.  2016.
• M. Coleman MP and A. Hoke. Programmed axon degeneration: from mouse to mechanism to medicine. Nat Rev Neuro. 2020.
• M. Clements et al. Generation of immunocompetent somatic glioblastoma mouse models through in situ transformation of subventricular zone neural stem cells. STAR protocols. 2024.
• H. Venkatesh et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Nature. 2015.
• V. Ravi et al. Neuronal integrin αvβ3 is a key regulator of glioblastoma invasion. Nature. 2022.
• J. Gerdts et al. SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. Science. 2015.
• J. Jun et al. Fully integrated silicon probes for high-density recording of neural activity. Nature. 2017.

Your background

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

Supervision and training

All students have a primary and subsidiary supervisor. Students are also supported by a Thesis Committee and will have extensive lab support from lab members.

Formal supervisory meetings will be (once weekly) with primary and secondary supervisors. The student will participate in the UCL CI CIRPS seminars, departmental seminars and weekly lab meetings in addition to the UCL teaching and training meetings.

All students are registered initially as an MPhil and take part in a compulsory first year Cancer programme. You are also part of the UCL Doctoral School’s Development Training Programme and take courses towards 20 training points per year.

UCL Cancer Institute offers numerous opportunities for scientific development that the student will be encouraged and supported to participate in.  This will be supplemented by generic professional skills/science-allied courses including, but not limited to:

• The UCL doctoral skills development programme
• Public and patient involvement
• Data curation and management
• Scientific writing and presentation skills
• Teaching workshops
• Self-management
• Intellectual property management.

We recognise the formative nature of the PhD experience, and therefore the student will be encouraged to explore their own areas of interest and development.

Entry Requirements

A UK undergraduate degree at First or Upper Second-Class UK Honours degree, or the equivalent qualifications gained outside the UK, in biological sciences is essential.

Candidates will need to demonstrate a strong research component ideally with some independent working. We are looking for a motivated, meticulous and scientifically curious student that can independently plan and perform experiments, and ensure that the results are recorded, analysed and written up in a timely fashion.

We value creativity, strong problem-solving abilities, and resourcefulness.

We welcome applicants from disadvantaged backgrounds, or via an unconventional career path so please feel free to explain that in your covering statement.

Essential experience: Practical experience in a range of basic molecular biology techniques, good presentation and scientific writing skills are essential.

English Language Requirements

If your education has not been conducted in the English language, you will be expected to demonstrate evidence of a good level of English proficiency. The English language level minimum for this programme is Level 3.

Deadline and Application Process

The deadline for submission is: 07 July 2025.

Interviews and selection will be online or in person in late July. Successful candidates will be invited to visit the laboratory and meet members of the team.

To apply please send your selection materials to ci.pgreducation@ucl.ac.uk.

1. A CV not exceeding two pages.
2. Two academic / professional references from scientists / academics who are familiar with your academic work and / or research experience and who can judge your potential as a PhD student.
   1. One should be your current or most recent academic employer / supervisor.
   2. At least one must be able to comment on your university academic record.
   3. At least one must be able to comment on your previous research experience.
   4. Please ask them to directly send the reference to ci.pgreducation@ucl.ac.uk from their institutional email account. We cannot accept reference letters sent by the candidates.
3. Transcript(s) of the marks you achieved in your qualifications.
4. In your one-page statement, please expand on:
   1. Why you want to do a PhD, and why this one in particular
   2. Your previous relevant research experience, including your experience with cell culture and wet lab techniques, molecular biology, and data analysis. Specify what your exact role was in any projects
   3. Your career aspirations.

Shortlisting will be immediately after the closing date. Please submit all your documents and ensure your referees have provided their references by this date so your application can be processed.

Shortlisted candidates only will be asked to apply formally through UCL.

We wish you every success in your application and we thank you for the interest in this PhD position.