MRC DiMeN Doctoral Training Partnership: Curing brain cancer one cell at a time: spatial, single cell transcriptomic analysis of glioblastoma brain tumour treatment response

Glioblastoma (GBM) is the deadliest type of adult brain cancer. Surgery cannot remove the whole tumour and, despite remaining cells receiving chemoradiation, some of them inevitably become treatment resistant leading to fatal tumour regrowth. Dr Lucy Stead, the primary supervisor, has discovered that patients separate into two groups depending on how their GBM tumours adapt to, and survive, the current standard of care treatment. This knowledge could be used to identify group-specific therapies (personalised medicine) to more effectively treat this currently incurable cancer. However, first we need to acquire an in-depth understanding of why and how two distinct treatment mechanisms occur. Different cancer cell types (defined by gene expression profile) exist within GBM tumours, and these have been shown to plastically alter their behaviour when treated, in ways dependent on the tumour microenvironment (TME). Bulk RNAseq indicates varied proportions of the cancerous and TME cell types in the two GBM subgroups and differences in how these populations change through treatment. To further characterise this, and identify therapeutic targets, we have performed spatial, single cell transcriptomics on multiple regions of paired pre- and post-treatment GBMs from patients of the different subgroups. Dr Rachel Queen, the second supervisor, is an expert in evaluating these specific datasets, having developed and released software packages for their analysis. The successful candidate for this project will be tasked with:

1)   Training in single cell spatial transcriptomics data analysis using existing software

2)   Further developing methods to be applicable to the bespoke dataset in hand

3)   Applying these methods to the existing multi-region paired longitudinal GBM data across patient sub-groups to identify personalised medicine targets of treatment resistance

This project is highly novel and timely. Cancer cell plasticity is one of the Cancer Research UK’s grand challenges of 2023 and has recently emerged as a major driver of GBM treatment resistance. Dr Stead holds the largest collection of paired primary and recurrent GBM samples in the UK, profiled at the bulk and single cell level to enable unprecedented characterisation of GBM cancer cell plasticity through treatment, to reveal novel therapeutic targets. Furthermore, spatial transcriptomics was Nature’s 2020 method of the year but development of the tools required to analyse these diverse datasets has lagged behind. Dr Queen is expert in developing methodology to maximise the biological insights from these datasets.

The successful candidate needs to be driven and self-motivated, keen to learn and develop cutting edge analysis technique and apply them in ways that can have real patient impact. This is a wholly computational biology project that would suit a person with an analytical mind and a passion for biomedical research.

To find out more please email the supervisors and visit https://medicinehealth.leeds.ac.uk/medicine/staff/789/dr-lucy-stead and https://braincancer.leeds.ac.uk/glioma-genomics/ and https://www.ncl.ac.uk/medical-sciences/people/profile/rachelqueen.html. You can also see us on Twitter at @LucyFStead, @GliomaGenomics or @rachelq_ncl

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog 

Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/how-to-apply