PhD Studentship: Modelling the epigenome in oral dysplasia and early invasive carcinoma

The key molecular events which lead to the development of premalignant oral lesions and their progression to oral cancer are still poorly understood. Much of the published research in this area has used well-defined cell culture models grown in monolayer which does not result in a physiological representation of the in vivo situation. In order to model this, tissue engineered mucosal constructs are a very useful tool, not only in allowing differentiation, but also in defining key events at the initiation of invasion. Identification of these key events may allow for the development of new diagnostics or therapeutic targets in early oral cancer, which would be very useful in reducing the continued poor survival seen in patients with this disease.

This project aims to address the following questions:

1. What are the differences/changes in the epigenome (methylation and miRNA expression) in TE models of dysplastic oral mucosa of varying grades, and also in those cells lines which invade?

This will be addressed using a panel of well-characterised oral dysplasia and SCC cell lines in our TE mucosal model system. The patterns of miRNA expression and methylation will be assessed in these tissues by TLDA array and EpiTect Methyl II Complete PCR Arrays, using constructs derived from cells with varying grade of dysplasia and early invasion into the underlying matrix. The results will be validated using standard PCR/Methylation specific PCR.

2. Does the phenotype of the fibroblast used to construct the model affect the epigenome of the TE mucosal models?

It is now well established that control of epithelial function occurs form a number of stromal cells, including fibroblasts. We will construct the TS mucosal models with varying fibroblast phenotype, including normal, those derived from dysplastic tissue and tumour associated fibroblasts. Assays will be similar to above.

3. Which epigenetically controlled molecular pathways are being altered as dysplasia progresses and invasion is initiated? What is their function in the cells?

Candidate biomarkers identified will be functionally analysed, initially in monolayer culture, and if promising, in TE mucosa after stable alteration of expression. This will allow for assessment of the effects on functions such as proliferation, migration, invasion, apoptosis and other pro-tumourigenic capabilities.

4. Can these changes be seen in a cohort of tissues form patients with oral dysplasia and early invasive SCC?

We have access to a wide range of oral biopsy tissues to validate the findings in a clinical context and to assess their potential utility as biomarkers. This will be done in tissues by immunohistochemistry or in situ hybridisation, as appropriate.


How to apply

Please apply through our online postgraduate application system including the Scholarship Application section where you need to tick the ’University Scholarships’ box. The form will ask you to summarise your research proposal in less than 800 words. If you are unsure about what to put in this section, please contact your prospective supervisor. Please name your supervisor and select their department (Clinical Dentistry) through the online form.

Deadline: Midnight 31st December 2016

Funding Notes

Funding

The Faculty of Medicine, Dentistry & Health Doctoral Academy Scholarships cover Home/EU fee and RCUK rate stipend for three years. Overseas students may apply but will need to fund the difference between the Home and Overseas fee from another source.

Proposed start date: October 2017

Candidates must have a first or upper second class honors degree or significant research experience

References

Relevant references
Colley HE, Hearnden V, Jones AV, Weinreb PH, Violette SM, Macneil S, Thornhill MH, Murdoch C. Development of tissue-engineered models of oral dysplasia and early invasive oral squamous cell carcinoma. Br J Cancer. 2011 Nov 8;105(10):1582-92.
Hunter KD, Thurlow JK, Fleming J, Drake PJ, Vass JK, Kalna G, Higham DJ, Herzyk P, Macdonald DG, Parkinson EK, Harrison PR. Divergent routes to oral cancer. Cancer Res. 2006 Aug 1;66(15):7405-13.
Profiling early head and neck cancer. Hunter KD, Parkinson EK, Harrison PR. Nat Rev Cancer. 2005 Feb;5(2):127-35.