Our laboratory is interested in delineating normal tissue homeostasis and understanding pathological changes during tissue repair and cancer. The major themes in the laboratory are the biological and molecular mechanisms of dysregulation of pathways involved in cell growth, migration, invasion, and intercellular communication during tumor development and progression. We are then exploring strategies for therapy of tumors and tissue damage.
Keratinocytes in the epidermis of the skin control proliferation of melanocytes and dictate which cell surface molecules are expressed for adhesion and migration. The lab's working hypothesis is that melanocyte proliferation is possible if they decouple from keratinocytes by down-regulating E-cadherin and its co-receptor desmoglein-1, which will interrupt gap junctions. Down-regulation of expression of the cell-cell communication molecules is mediated through the production of HGF, ET-1, and PDGF. The melanocytes then retract their dendrites that had connected them to keratinocytes of the suprabasal layers by activating rac and rho genes. Cell division is likely initiated through activation by keratinocyte-derived growth factorssuch as bFGF, SCF, ET-1 or by fibroblast-derived factors such as HGF, IGF-1, or ET-3. After cell division, melanocytes separate and glide over the basement membrane using integrins such as alpha6ß1 or alpha7ß1 before repositioning singly among basal layer keratinocytes. Using the three-dimensional organotypic culture model of human skin consisting of dermis and epidermis we are retracing each step in the proliferation cascade of melanocytes to better understand dysregulation of growth and cell-cell communication in melanoma. The lab uses adenoviral and lentiviral vectors to transfer genes for overexpressing or inhibiting a function of interest. The unique model of human skin reconstruction in vitro and in vivo allows us to investigate signaling between melanocytes and keratinocytes for tissue homeostasis and its dysregulation during transformation to nevi and melanomas. Melanoma cells have escaped from keratinocytes by downregulating E-cadherin and upregulating N-cadherin. The cadherin switch allows a cell partner change because now melanoma cells can adhere through N-cadherin to fibroblasts and endothelial cells. Overexpression of E-cadherin in melanoma cells allows keratinocytes to adhere to them and regain control over proliferation and the expression of cell surface molecules, so the malignant cells revert to a non-malignant phenotype. The team expects in the next few years to identify and characterize transcriptional activators or repressors in normal melanocytes that are non-functional in melanoma cells but can be reactivated to control growth and invasion.
Melanocyte homeostasis in normal human skin. Cell division for melanocytes likely begins with the upregulation of growth factors produced by either fibroblasts or keratinocytes, which lead to down-regulation of cadherins and decoupling of melanocytes from keratinocytes. Mitogenesis is driven by other growth factors from dermis or epidermis. Migration for repositioning, anchorage to the basement membrane, re-coupling to keratinocytes, dendrite extension into the upper cell layers, and growth control by keratinocytes complete the cycle for melanocytes to maintain a stable ratio with epidermal keratinocytes. Repositioning of melanocytes to the new location on the epidermal basal layer and their re-coupling with keratinocytes is intitated with cadherin mediated binding.