Extracellular Vesicles: small packages with a big role in bowel cancer metastasis

Project details
Background: Patients with metastatic colorectal cancer (CRC) have poor survival rates, reflecting the difficulty in treating advanced disease. The events that lead to CRC metastases establishing are poorly understood; recently it has been proposed that extracellular vesicles (EVs) condition metastatic sites through organ-specific uptake. This project will determine the molecular processes driving metastasis and the role of EVs, aiming to develop new treatment approaches for advanced disease and to support monitoring and diagnosis of metastatic CRC.

Aims: 1) Develop a detailed understanding of CRC metastasis. 2) Develop an understanding of how/why CRC metastasises to particular sites. 3) Determine how EVs contribute to CRC metastasis.

Methods: Organotypic models of metastatic sites will be developed, which will be analysed histologically, biomechanically, and proteomically to develop signatures linked to metastatic progression. Models will also be conditioned using EVs from CRC cells, and the impact of this conditioning on invasion and metastatic signatures will be assessed. Micro-RNA profiles of EVs will be characterised and linked to their effects. These effects will then be validated in CRC tissues.

Outcomes: We will develop molecular signatures of metastatic progression in vitro, linked to histological and biomechanical features of tissue remodelling. Identifying key pathways linked to metastasis and important site-specific features will provide a basis for treatment approaches. We will use molecular manipulation to assess the putative role of a key mediators of invasion identified in this profiling, including the important enzyme TG2. We will then link EV miRNA profiles to their effects, identifying potential biomarkers of metastasis.

Research Environment
The project will benefit from extensive culture and 3D modelling facilities in the Biomolecular Sciences Research Centre, and MALDI-imaging technology in the Centre for Mass Spectrometry Imaging at SHU. Dr Peake and Professor Le Maitre are established researchers with vast experience of developing in vitro models of disease and will provide full training. Dr Cole is an expert in MALDI imaging and complementary analytical techniques which will be used to develop molecular signatures in the model. The student will also benefit from working with established collaborators at the University of Sheffield and the University of Southampton, who will provide support for extracellular vesicle isolation and analysis, and clinical samples for translational impact.
https://www.shu.ac.uk/research/specialisms/biomolecular-sciences-research-centre
https://www.shu.ac.uk/research/specialisms/biomolecular-sciences-research-centre/what-we-do/commercial-services/mass-spectrometry


Entry requirements
Successful applicants will possess all of the attributes listed below.
• A first class or upper second class honours degree in cancer biology, molecular biology, cell biology, protein biology or a related discipline or a distinction at MSc.
• Experience working in a research laboratory in a relevant field.
• Excellent communication skills in English (speaking and writing).
• Ability to work independently and within a team.
• Highly motivated with a commitment to conduct high quality research.
• Excellent time management skills.