FULLY FUNDED - Does radiotherapy of glioblastoma lead to unwanted promotion of invasive microenvironments in the brain via extracellular vesicle-mediated mechanisms?

   College of Medical, Veterinary and Life Sciences

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  Dr Joanna Birch, Prof Jim Norman, Prof V Brunton  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

'To apply, please click institution web link'*

Glioblastoma is the most common and aggressive form of primary brain tumour. Despite maximal surgical resection followed by radiotherapy (RT) and chemotherapy, median survival remains stubbornly low at only 12-15 months post diagnosis due to inevitable recurrence. This is in part due to the ability of GBM cells to infiltrate the normal brain at the invasive edges of the tumour, rendering complete surgical resection impossible. This microscopic infiltration can also reach vital structures of the brain such as the brain stem, producing devastating and life-threatening symptoms. The identification of novel therapeutic targets to oppose invasion have the potential to prolong survival and alleviate symptoms in GBM patients.

While RT is a highly effective treatment for solid cancers, it has also been demonstrated to can induce changes to cytoskeletal plasticity via RhoGTPases that impart a more invasive phenotype on surviving cancer cells. Previous work from the Birch group indicated that targeting this unwanted pro-invasive effect of radiotherapy in GBM led to improved efficacy of RT and prolonged survival in a clinically-relevant mouse model (1). Together with a collaborator, Ross Carruthers, they also identified the ATR kinase – a key component of the DNA damage response pathway - as a factor that links the DNA damage triggered by RT to the cytoskeletal changes necessary to drive invasion of GBM(2).

Recent work from the Norman and Birch groups have found that GBM cellscan influence the surrounding brain microenvironment by releasing extracellular vesicles (EVs) which encourage glial cells (such as astrocytes) to alter the hyaluronic acid content of the extracellular matrix (ECM) that they deposit. (3). As the trafficking and release of EVs into the extracellular environment, and their uptake into recipient cells, requires dynamic cytoskeletal processes, we hypothesise that EV release and uptake will be upregulated in response to RT. Thus, EVs produced by GBM cells in response to RT-induced damage have the potential to evoke changes on both neighbouring GBM cells, and normal parenchymal cells at the infiltrating tumour margin and beyond to promote an invasion-permissive environment.

To investigate this hypothesis, the candidate will use a combination of cell biology techniques, advanced imaging and preclinical in vivo models to address the following questions:

1) What is the capacity for radiation to drive EV release from GBM?

2) How do DNA damage sensing mechanisms initiate this response?

3) Do exosomes from irradiated GBM influence treatment-naive GBM or parenchymal cells to alter their migration, proliferation, and ECM deposition at the infiltrative tumour borders and in more distant regions brain?

4) What role do RhoGTPases and their control of the cytoskeleton play in EV release from irradiated and the responses neighbouring GBM and glial cells to these EVs?

*You must download and complete the below form with your application.

 CRUK_Scotland_Centre_recruitment form.docx

Biological Sciences (4)

Funding Notes

Applications are open to all individuals.
PhD studentship available to start in October 2023 for an outstanding applicant with a stipend of £21,000 p/a. This will be funded by the CRUK Scotland Centre, a joint initiative between the University of Edinburgh and the University of Glasgow.
Please note that applicants are not required to submit a research proposal when completing the online application. The CRUK EDI form is required for the process of application. please complete and upload on the Applicant Self-Service Portal.
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