In the human epidermis, melanocytes and keratinocytes maintain a lifelong homeostatic balance, which is only disturbed during transformation. Keratinocytes are the master regulators over normal melanocytes controlling their growth and expression of cell surface receptors associated with adhesion and migration. Melanoma cells, on the other hand, escape from keratinocyte-mediated control by down-regulating expression of the cell-cell adhesion receptor E-cadherin and establishing gap junctions with fibroblasts in the dermis. Forced expression of E-cadherin in melanoma cells re-establishes the control of keratinocytes over growth and expression of invasion-related cell surface adhesion receptors, leading to a reversion of the malignant phenotype. To better understand how keratinocytes regulate the phenotype of melanocytes and E-cadherin expressing melanoma cells, the cell-cell communication and signaling between the two cell types will be investigated. (1) In the normal melanocytes resting in the epidermis of a human skin equivalent, the cell surface molecules that are suppressed by keratinocyte-mediated control as well as those that act as co-receptors for E-cadherin-mediated cross-talk will be identified. To achieve nevus- and melanoma-like lesions in the skin equivalents, adhesive interactions of the normal melanocytes with keratinocytes will be disrupted, then inducing them to retract their dendrites, followed by stimulation of cell division and re-positioning along the basement membrane. Replication defective adenoviral vectors will be used for abrogation or induction of gene expression or function. (2) Uncontrolled proliferation of melanocytes will be achieved in equivalents of human skin in vitro and in vivo by switching adhesive interactions of melanocytes from keratinocytes to fibroblasts and by transducing survival factors into the melanocytes to allow keratinocyte-independent proliferation. (3) The mechanisms of regulatory control of keratinocytes over melanocytes and E-cadherin expressing melanoma cells will be investigated by dissecting the cadherin/catenin signaling pathway, which will be targeted with genetic suppressor elements (GSE). As additional signaling pathways are being defined, therapeutic strategies that would mimic the regulatory control of keratinocytes over E-cadherin-expressing melanoma cell will be developed as a long-term objective.
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