Human skin has a unique architecture that is intimately related to the functions of its cellular constituents. In the epidermis, melanocytes reside at the basement membrane and are interspersed among basal layer (undifferentiated) keratinocytes. The spatial and functional synergy between normal melanocytes and keratinocytes is disturbed during melanocyte transformation. Keratinocytes can control the phenotype of normal melanocytes, but not that of advanced primary and metastatic melanoma cells, regarding expression of cell surface molecules, cell shape and cell growth. The inability of keratinocytes to influence melanoma coincides with: i) loss of E-cadherin and upregulation of N-cadherin expression, both of which are calcium-dependent homophilic adhesion molecules; and ii) reduction, or even loss, of the ability to couple the keratinocytes through gap junctions. Instead, melanoma cells develop inter-cellular communications via gap junctions with dermal fibroblasts which express functional N-cadherin. Based on these dynamic changes in inter-cellular interactions during transformation, the applicant will explore the role of E-cadherin in melanocyte-keratinocyte signaling and epidermal morphogenesis. Dysfunctional E-cadherin signalling in the epidermis, which frees melanocytes from keratinocyte contact-mediated regulatory controls, may lead to proliferation of melanocytes. Restoration of E-cadherin expression in melanoma cells may reverse the malignant phenotype due to the """"""""invasion suppressor"""""""" activity of this adhesion receptor. The switch in melanoma cells from E- to N-cadherin expression apparently increases cell scattering and allows adhesion and communication of the malignant cells with stromal fibroblasts. It remains to be determined whether cadherins not only mediate cell docking but allow regulatory signaling through separate pathways such as gap junctions or growth factor receptor/ligand activation. This proposal addresses the biological significance of inter-cellular signaling during distinct steps of melanoma tumor progression.
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