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Does fatty acid uptake by oral cancer cells drive metastasis?


Project Description

The cell surface receptor CD36 belongs to a large scavenger receptor family that primarily bind lipid-containing molecules. Until recently their expression was thought to be restricted to macrophages and endothelial cells but recent data suggest that epithelial cancer cells may also express this receptor. Data from our laboratory shows that oral squamous cell carcinoma (OSCC) cells express high levels of CD36 and upon binding to its ligand, oxidized low density lipoprotein (oxLDL), these cells activate intracellular signaling pathways (JNK) that mediate loss of adherence and increased cell migration, suggesting a role for CD36 in epithelial to mesenchymal transition (EMT) and metastasis. Taken together, these data suggest that up-take of dietary lipids by OSCC cells may aid tumour cell metastasis, potentially linking obesity to disease progression.

In this project you will perform a variety of experiments such as culture of CD36-positive, CD36 knock-out OSCC cells, normal oral keratinocytes (NOK) and NOK overexpressing CD36 with oxLDL or a range of dietary fatty acids (e.g. palmitic acid) and examine if this receptor regulates expression of a panel of EMT markers by RT-qPCR and immunoblotting. You will also incubate CD36-positive OSCC with blocking antibodies and/or JNK inhibitors before culture with lipids before examining expression of EMT markers and OSCC cell migration. In parallel, you will examine the expression of CD36 on a large cohort of paired human primary and metastatic OSCC available in our department using immunohistochemistry, and correlate this with clinical data to determine of CD36 expression is linked to poor outcome, tumour stage or metastatic risk.

Murine models of OSCC metastasis are relatively poor because orthotopic cancer models are restricted by the small size of the murine oral cavity and subcutaneous OSCC tumours do not represent the disease pathology. Our laboratory has extensive expertise in producing tissue engineered OSCC 3D models where cancer cell invasion and migration into collagen gels can be visualized and measured. You will use these models to assess a variety of drugs that may prevent CD36-mediated metastasis.

It is likely that up-take of high-energy lipid molecules by CD36-expressing cancer cells may dramatically alter their gene expression, in particular metabolic and plasma membrane synthesis pathways that are required for increased energy production required for motility and cell proliferation. To address the lack of data in this area you will perform global gene expression profiling on OSCC cells in the absence or presence of oxLDL and use bioinformatics tools to assess genes and pathways affected by lipid up-take, which will lead to new pathways of research in this area.

The combined findings of these studies will fill the knowledge gap in this area of research as well as identifying potential therapeutic agents.

Enquiries:
Interested candidates should in the first instance contact (Dr Craig Murdoch )

How to apply:
Please complete a University Postgraduate Research Application form available here: http://www.shef.ac.uk/postgraduate/research/apply

Please clearly state the prospective main supervisor in the respective box and select School of Clinical Dentistry as the department.

Funding Notes

This project is open to self-funded students only.

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