Melanoma is a highly aggressive cancer that begins in melanin-producing melanocytes in the skin. It accounts for only about 1% of skin cancers, but it is the leading cause of skin cancer deaths. US military personnel have higher rates of melanoma than civilians because of the heavy exposure to sunlight in the deployment setting. Based on the Veterans Affairs Central Cancer Registry, melanoma is one of the five most frequently diagnosed cancers among VA cancer patients. US Veterans will continue to be vulnerable to melanoma as the US military currently is and has been recently engaged in missions in several high ultraviolet (UV) index zones, such as Iraq and Afghanistan. Thus, there is a critical need to devise strategies to slow melanoma progression, leading to extended or even permanent survivorship in Veteran patients. Current efforts in melanoma research are heavily focused on blocking cell proliferation or killing tumor cells. However, it may also be possible to treat this disease by preventing tumor cells from spreading to other organs. The planar cell polarity (PCP) pathway controls tissue polarity during development by regulating the directional movement of cells and coordinating neighboring cells to the tissue axes. Increasing evidence suggests that it also plays a role in cancer by promoting tumor cell migration and invasion. Although some information is available regarding the PCP pathway in certain cancers, its involvement in melanoma has not been studied. The long-term goal of our study is to dissect the role and mechanism of the PCP pathway in melanoma development and progression. In our preliminary studies, we have found that Frizzled 6 (FZD6), one of the core PCP genes, is overexpressed in multiple melanoma cell lines and human tissues. Knockdown (KD) or knockout (KO) of FZD6 does not affect cell proliferation, but significantly reduces the invasive ability of melanoma cells. In addition, we have found that KO of Fzd6 dramatically reduces lung metastasis in the Pten/BRaf mouse model of melanoma. Therefore, we hypothesize that FZD6 promotes melanoma invasion and metastasis by regulating cell polarity and could serve as a novel target for melanoma management. We will test this hypothesis with the following three aims: (1) to determine the mechanisms of FZD6 in promoting melanoma cell invasion in vitro; (2) to determine the functional significance of FZD6 in melanoma metastasis in vivo; and (3) to determine the clinical relevance and therapeutic significance of FZD6 in melanoma. The proposed research is innovative. We have assembled a team with diverse expertise to take a multi-disciplinary approach using loss- and gain-of-function genetic studies, live-cell imaging, inducible protein degradation, genomics, and drug discovery. The proposed research is significant. Our proposed aims will not only unveil mechanistic insights into the FZD6-mediated PCP pathway in promoting melanoma metastasis, but serve as proof-of-principle studies for ...