Background
There is a pressing need for improvements in biological understanding and treatments for brain cancer. Progress has been particularly poor for glioblastoma (GBM), the most aggressive form of adult brain cancers. Despite aggressive treatment, including surgical resection, chemotherapy, and radiotherapy, the median overall survival remains only 12–18 months. Although whole genome sequencing has revealed the complexity of the mutational landscape, it has not yet yielded tractable precision medicine hypotheses that have changed clinical treatment. Whereas tumours used to be thought of as a clonal population of one malignant cell type, we now know that they behave more like a tissue, with heterogeneous malignant cells cooperating with multiple different non-cancerous stromal cell types and extracellular matrix proteins, to orchestrate intracellular cues that drive tumour progression and treatment resistance. GBMs are diffusely infiltrative, with migrating cells outside the tumour core being resistant to treatments and responsible for the inevitable recurrences in GBM patients. Understanding and modelling the complex interaction between GBM and the surrounding microenvironment that drives the invasive nature of the disease will be key to providing new therapeutic options.
Aims
1. To provide a spatial annotation of the structural microenvironment in clinical samples of GBM focussing on the tumour vasculature and extracellular matrix components.
2. To annotate and optimise organotypic models of freshly resected GBM material to provide tractable models for analysing how disruption of the tumour microenvironment impacts on invasive capacity and response to therapy
Project outline
Multi-photon and multiplex immunofluorescence imaging will be used to characterise the interaction of tumour cells with the tissue vasculature, surrounding extracellular matrix proteins (e.g. collagens, hyaluronic acid) in human GBM samples collected at surgical resection. Quantitative approaches will be developed and used to compare the tumour microenvironment within the tumour body and at the invasive margins, mapping this to areas of hypoxia and markers of tissue stiffness. This will be combined with analysis of cytokines and matrix proteins secreted from GBM derived cell lines and normal neuronal stem cells using forward phase protein arrays and proteomics approaches, to identify tumour-derived factors that contribute to the tumour microenvironment. Bioinformatic approaches will be applied to identify highly connected and likely functional nodes in the tumour-dependent secretome. Immunocytochemistry will be carried out to establish their expression and relevance in human GBM.
Developing models of GBM that faithfully recapitulate the human disease is critical to understanding the complex biology that governs GBM behaviour and response to therapy. Organotypic and 3D spheroid models using freshly resected tissue and GBM-derived cell lines will be established and characterised for viability, invasive capacity and the ability to carry out temporal studies. Image analysis pipelines will be developed and validated to allow interactions between tumour cells and the surrounding environment to be monitored and quantified. These will be used to determine the functional relevance of the GBM-dependent secretome by using gene editing and pharmacological approaches to interfere with their function. This will provide mechanistic insight into how changes in the tumour microenvironment alters GBM invasiveness and response to therapy, with lead hits being followed up in mouse models of GBM.
Training outcomes
This studentship will provide interdisciplinary training in computational biology, image analysis and quantification, molecular biology, proteomics and 3D modelling.
About the Programme
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.
http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919
Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.
For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine
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