Cutaneous melanoma arises from melanocytes, but the identity and transformation potential of distinct melanocyte subpopulations remain unclear. Our preliminary scRNA-seq analyses of human skin identified an NTRK2+ melanoblast-like population that selectively expands following UVR exposure, suggesting heightened susceptibility to transformation. Complementary analyses of melanoma datasets reveal NTRK2 expression in tumor cells enriched for invasive, mesenchymal, and neural crest-like programs associated with stemness and therapy resistance. These findings suggest that NTRK2+ cells may represent a high-risk population critical to melanoma initiation and progression. We therefore hypothesize that thistranscriptionally unique melanocyte progenitor population, marked by high NTRK2 expression, serves as a cell-of-origin for melanoma due to its distinctive survival and proliferative response to UV, and that malignant NTRK2+ counterpart supports tumor invasion and therapy resistance. This project aims to define the contributions of NTRK2 expression in melanocytes to early melanomagenesis and in melanoma cells to disease progression, ultimately identifying biomarkers and molecular targets for preventive and therapeutic intervention. To further characterize this, we are developing a 3D melanocyte-enriched human skin equivalent (mHSE) model incorporating fibroblasts, keratinocytes, and melanocyte subpopulations or melanoma cells. This UVR-treatable system will recapitulate native skin architecture and melanoma-microenvironment interactions,enabling prospective studies of subpopulation-specific responses to UVR and anti-cancer therapies. Through such engineered tissue modelling, this project will reveal mechanisms driving melanocytic transformation, disease evolution, and therapy resistance. Moreover, we will establish an animal-free platform for functional studies and preclinical testing of targeted strategies, with the long-term goal of intercepting melanoma before tumor formation or progression. Data will be presented to indicate progress on development of our mHSE model.