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.
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
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 for at least one year is desirable.
• 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
This is a 3 year fully funded PhD studentship. The studentship covers home/EU tuition fees (£4,260 in 2018/19) plus a generous stipend equivalent to the full UK Research Innovation rate of £14,777.
This PhD is primarily funded by Bowel & Cancer Research, with additional support from the SHU "creating knowledge" collaborative PhD scheme.
Interested candidates should apply to Sheffield Hallam University via the University application form, including a 1500 word research proposal (section 9) demonstrating your background reading on the topic of the PhD and your plans for how you would undertake this programme of research. Additionally please include a covering letter describing why you are interested in pursuing postgraduate studies and how you meet the selection criteria.
An application form can be downloaded at the following URL:
For informal enquiries about the project please contact Dr Nick Peake: [email protected]
• Deadline for applications 31st March, 2019
• Interviews will be held in April
• Studentship to begin in May, or in exceptional circumstances, October.