Transformation of human melanocytes and mechanisms of melanoma metastasis

Abstract

While a fundamental feature of human melanoma is its tendency to metastasize to numerous organs throughout the body, very few animal models recapitulate this essential aspect of the disease. In the work described, it is demonstrated that human dermal melanocytes, transformed by the introduction of the SV40ER, hTERT, and RasG12V genes, form primary tumors that are invasive and highly metastatic to secondary sites in the body. Moreover, the anatomical sites of metastasis exhibited by the melanoma cells created in this manner are analogous to those observed in human patients. The introduction of an identical set of genes into human epithelial and fibroblast cell types results in localized tumor formation in the absence of metastasis. These observations indicate that part of the metastatic proclivity of melanoma is attributable to lineage-specific factors expressed in melanocytes but not in other cell types. Analysis of microarray data from human nevi reveals that Slug, a master regulator of neural crest cell specification and migration, correlates in its expression pattern with other genes that are important for neural crest cell migration during development. Moreover, Slug is required for the metastasis of the transformed melanoma cells. These findings indicate that melanocyte-specific factors present prior to neoplastic transformation can play a pivotal role in governing melanoma's progression.