1266 The role of planar cell polarity gene FZD6 in melanoma progression

Abstract

Melanoma is the malignant tumor of melanin-producing melanocytes in the skin. It is the leading cause of skin cancer deaths. Despite recent progress in melanoma therapeutics, the prognosis remains very poor due to the low response rate to drugs and the rapid distant metastasis in patients. A broader understanding of the biology of melanoma, especially how tumor cells metastasize, is needed to develop effective treatments for this devastating disease. The planar cell polarity (PCP) pathway controls tissue polarity during development by regulating the directional movement of cells and coordinating neighboring cells to the body/tissue axes. Increasing evidence suggests that it also plays active roles in cancer by promoting tumor cell migration and invasion. Although limited information is available regarding PCP pathway in certain cancers, its involvement in melanoma development and progression has not been studied. In our preliminary studies, we found that Frizzled6 (FZD6), one of the core PCP genes, is overexpressed in multiple human melanoma cell lines. SK-MEL28 has the highest level (over 90-fold compared to normal adult human epidermal melanocytes). To determine the role of FZD6 in melanoma cells, we made FZD6 knockout SK-MEL28 melanoma cell lines using CRISPR/Cas9. We found that knockout of FZD6 significantly reduces the migration ability of melanoma cells (using in vitro wound healing assays), while tumor cell proliferation is not affected. Current studies are underway to determine the role of FZD6 in melanoma metastasis using genetically engineered mouse models. We are also investigating the downstream mechanisms of FZD6 using both candidate approaches and non-biased transcriptome analysis. Our study will not only provide insights into the role of FZD6 in melanoma progression but also set the stage for additional studies to identify the role of other PCP genes in melanoma. The information generated from these studies will substantially broaden our knowledge on the biology of melanoma and might lead to novel therapeutic approaches for melanoma.