PhD Studentship: Does fat contribute to oral squamous cell carcinoma progression?

University of Sheffield - School of Clinical Dentistry

Obesity has been identified as a risk factor for a number of cancers, but its contribution to oral cancer (predominantly comprised of oral squamous cell carcinoma) outcomes is unclear. In some cancers, such as those of the prostate and breast, the presence of local fat (adipose) tissue (comprised mainly of adipocytes) correlates with disease progression, an observation supported by cell biology studies which identify an important role for adipose tissue in acting as a pseudo-endocrine system, releasing a variety of ‘adipokines’ which directly modulate cancer cell behaviour. Although adipose tissue is relatively sparse in the areas of the oral cavity most commonly harbouring OSCC, it is prominent around its most common site of metastatic colonisation, the cervical lymph nodes. Approximately (?%) of OSCC metastasise to cervical lymph nodes, and local spread from these deposits (extra-capsular spread; ECS) is a common cause of treatment failure and mortality in these patients. The mechanisms underlying ECS are poorly understood, hampering development of effective treatments and the identification of patients most at risk of developing this devastating sequela of OSCC. In light of the findings in other cancers in which adipose tissue is prominent locally, we hypothesise the adipocytes influence the behaviour of metastatic OSCC cells in lymph nodes to favour extracapsular spread.

In this project you will help test this hypothesis by examining the effect of adipocyte-derived factors on the behaviour of OSCC cells, derived from both primary tumours (OSCC) and lymph node metastases (LN-OSCC), and other cell types known to influence OSCC progression and ECS. You will initially analyse the effect of conditioned media collected from adipocytes in culture on the migration and invasion of OSCC and LN-OSCC cells in vitro, and use qPCR and western blotting to determine levels of markers associated with aggressive tumours such as transcription factors promoting epithelial-mesenchymal transition (EMT). You will also test the effect of this CM on the migration of inflammatory cells and the differentiation of fibroblasts; both of these cell types are important components of the tumour microenvironment that are known to contribute to OSCC growth and metastasis. If effects on all or any of these cell types are observed, neutralising antibodies and receptor antagonists to adipokines known to be released by adipocytes (such as CCL7/CCR3) will be utilised to determine the precise factors involved. Finally, the effects of adipose tissue derived from oral cancer patients on OSCC, fibroblast and immune cell behaviour will be examined as described above.

This project will be the first to examine whether adipose tissue contributes to oral cancer progression and may identify new prognostic indicators and opportunities for therapeutic intervention.

Entry Requirements

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

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Northern England