Planar Cell Polarity Control in Melanoma Metastasis

黑色素瘤是一种高度侵袭性的癌症，始于皮肤中产生黑色素的黑素细胞。IT帐目 只有大约1%的皮肤癌患者，但它是皮肤癌死亡的主要原因。美国军事人员已经 由于在部署环境中大量暴露在阳光下，黑色素瘤的发病率比平民更高。 根据退伍军人事务中心癌症登记处的数据，黑色素瘤是最常见的五种诊断之一 VA癌症患者中的癌症。美国退伍军人将继续易患黑色素瘤 目前正在并最近一直在伊拉克等几个高紫外线指数区执行任务 还有阿富汗。因此，迫切需要制定策略来减缓黑色素瘤的进展，从而导致 延长甚至永久存活的退伍军人患者。目前在黑色素瘤研究方面的努力很大 专注于阻止细胞增殖或杀死肿瘤细胞。然而，也有可能治疗这种疾病。 通过防止肿瘤细胞扩散到其他器官。平面细胞极性(PCP)途径控制组织 通过调节细胞的定向运动和协调相邻细胞来调节发育过程中的极性 到组织轴上。越来越多的证据表明，它还通过促进肿瘤细胞在癌症中发挥作用。 移民和入侵。虽然关于某些癌症中的PCP途径有一些信息， 它与黑色素瘤的关系还没有研究过。我们研究的长期目标是剖析 PCP途径在黑色素瘤发生发展中的作用机制。在我们的初步研究中，我们有 发现核心PCP基因之一Frizzled6(FZD6)在多种黑色素瘤细胞系和 人体组织。FZD6基因敲除(KD)或敲除(KO)不影响细胞增殖，但显著 降低黑色素瘤细胞的侵袭能力。此外，我们还发现Fzd6的KO显著降低 PTEN/BRAF小鼠黑色素瘤模型的肺转移。因此，我们假设FZD6促进 黑色素瘤通过调节细胞极性侵袭和转移，可作为治疗的新靶点 黑色素瘤管理。我们将通过以下三个目标来检验这一假说：(1)确定 FZD6促进黑色素瘤细胞体外侵袭的机制；(2)确定其功能意义 FZD6在黑色素瘤体内转移中的作用；以及(3)确定其临床相关性和治疗意义 FZD6在黑色素瘤中的表达。提出的研究具有创新性。我们已经组建了一支拥有不同专业知识的团队 采用多学科方法，使用功能丧失和功能获得的遗传学研究，活细胞成像，诱导性 蛋白质降解、基因组学和药物发现。这项拟议的研究具有重要意义。我们提出的目标 不仅揭示了FZD6介导的PCP通路促进黑色素瘤的机制 转移，但作为针对黑色素瘤的药物开发的原则验证研究 管理层。由于退伍军人患恶性黑色素瘤的风险更高，我们的工作是 对我们退伍军人的医疗保健具有重要意义。

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 drug development to target this system for melanoma management. Since the Veteran population are at higher risk of developing malignant melanoma, our work is relevant and significant to the health care of our Veterans.