We have shown that Wnt5A is a molecule that is important in the progression of melanoma cells to a highly metastatic state. Recently we have demonstrated that Wnt5A acts via the orphan tyrosine kinase receptor, ROR2, and that this interaction is modulated by heparan sulfate proteoglycans such as syndecan 4. The signaling of Wnt5A involves changes in the cytoskeleton, activation of an epithelial to mesenchymal transition and the loss of immunogenicity via the downregulation of melanocyte differentiation antigens and pigment. These features are consistent with a de-differentiation phenotype of melanoma cells. Given recent data that suggested that the Wnt protein, Wnt5A, can affect the proliferation and maintenance of hemaopoietic stem cells, we are trying to determine what the role, if any, of Wnt5A in the maintenance and profileration of the melanoma stem cell might be, and how this relates to the role of Wnt5A in melanoma metastasis.