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The ADAMs family of proteins are unique in that they possess both A Disintegrin and Metalloprotease domain so potentially have multiple functions in cell adhesion via their integrin‐binding domain and extracellular matrix degradation/cell invasion/protease and/or growth factor activation via their metalloprotease domain. The ‘knock‐out’ of ADAM‐10 expression in the mouse is phenotypically lethal. This is due to the absolute requirement for ADAM‐10 during early embryo development. ADAM‐10 has many crucial functions at this time including the activation of growth factors and the regulation of the cell adhesion molecules, cadherins.
Recent studies strongly implicate the down‐regulation of E‐cadherin as a rate‐limiting step in the Epithelial to Mesenchymal Transition (EMT). The EMT occurs during early embryo development in the formation of the germ layers and is also implicated as a precursor to the ability of cancer cells to metastasise from a primary tumour to a secondary or metastatic site. Increased cancer cell migration and invasion capabilities are also precursors to metastasis.
Recent studies have revealed that ADAM‐10 is significantly up‐regulated in metastatic melanomas compared to primary melanomas and that ADAM‐10 stimulates the migration of primary melanoma cells. Furthermore, the down‐regulation of ADAM‐10 expression reduced cell migration and suppressed anchorage‐independent cell growth in melanoma cells. Control of the metastatic spread of melanoma cells represents a major clinical challenge; therefore the inhibition of ADAM‐10 may represent a therapeutic solution.
The objective of this Honours project will be to assess the functional effects of a synthetic metalloprotease inhibitor of ADAM‐10 on human melanoma cell lines with different metastatic potentials. These cells will be treated with different concentrations of our inhibitor and cellular responses assayed using standard migration and EMT assay techniquess. Melanoma cells with and without inhibitor will also be evaluated in our 3D human skin equivalent model, to determine the effect on melanoma cell migration and invasion in skin tissue.