Planar Cell Polarity Control in Melanoma Metastasis

黑色素瘤转移中的平面细胞极性控制

• 批准号: 10360007
• 负责人: Hao Chang
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360007
• 关键词: Afghanistan; Alleles; BRAF gene; Behavior; Blocking Antibodies; Cancer Patient; Cell Line; Cell Polarity; Cell Proliferation; Cells; Cessation of life; Chimera organism; Cleft Palate; Cyclin D1; Defect; Development; Diagnosis; Disease; Disease Outcome; Distant Metastasis; Ectopic Expression; Exposure to; Future; Gelatinase A; Genes; Genetic study; Genomics; Goals; Healthcare; Human; In Vitro; Iraq; Knock-out; Lung; Lysosomes; MEKs; Malignant Neoplasms; Mediating; Melanins; Melanoma Cell; Metastatic Neoplasm to the Lung; Military Personnel; Mission; Modeling; Monitor; Mus; Neoplasm Metastasis; Neural Tube Defects; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Polycystic Kidney Diseases; Process; Proteins; Ras/Raf; Recurrence; Research; Role; Sampling; Signal Pathway; Skin; Skin Cancer; Skin Neoplasms; Sunlight; System; Technology; Testing; Therapeutic; Tissue Microarray; Tissues; Transgenic Mice; Tumor Cell Migration; United States Department of Veterans Affairs; Veterans; Work; base; cancer diagnosis; cell killing; cell motility; clinically relevant; congenital heart disorder; deafness; drug development; drug discovery; epithelial to mesenchymal transition; experimental study; gain of function; high risk; human disease; human tissue; in vivo; indexing; innovation; insight; interdisciplinary approach; knock-down; liquid crystal polymer; live cell imaging; melanocyte; melanoma; military veteran; mouse model; mutant; neoplasm registry; neoplastic cell; novel; novel strategies; overexpression; patient derived xenograft model; planar cell polarity; prevent; programs; prospective; protein degradation; survivorship; transcriptomics; ultraviolet

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.

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色素细胞。它占 仅占皮肤癌的 1% 左右，但却是皮肤癌死亡的主要原因。美军人员有 由于部署环境中大量暴露在阳光下，黑色素瘤的发病率高于平民。 根据退伍军人事务中心癌症登记处的数据，黑色素瘤是五种最常诊断的癌症之一 VA 癌症患者中的癌症。随着美国军队的进步，美国退伍军人将继续容易患黑色素瘤 目前并且最近一直在几个高紫外线 (UV) 指数区域执行任务，例如伊拉克 和阿富汗。因此，迫切需要制定减缓黑色素瘤进展的策略，从而导致 退伍军人患者的生存期延长甚至永久。目前黑色素瘤研究的努力主要集中在 专注于阻止细胞增殖或杀死肿瘤细胞。不过，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) 通路控制组织 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。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 迁徙和入侵。尽管有一些关于某些癌症中 PCP 途径的信息， 尚未研究其与黑色素瘤的关系。我们研究的长期目标是剖析角色和 PCP途径在黑色素瘤发生和进展中的机制。在我们的初步研究中，我们有 发现核心 PCP 基因之一卷曲 6 (FZD6) 在多种黑色素瘤细胞系中过度表达，并且 人体组织。 FZD6 的敲低 (KD) 或敲除 (KO) 不会影响细胞增殖，但会显着影响细胞增殖。 降低黑色素瘤细胞的侵袭能力。此外，我们发现 Fzd6 的 KO 显着降低了 Pten/BRaf 小鼠黑色素瘤模型中的肺转移。因此，我们假设 FZD6 促进 通过调节细胞极性来抑制黑色素瘤的侵袭和转移，并可作为治疗黑色素瘤的新靶点 黑色素瘤管理。我们将通过以下三个目标来检验这个假设：（1）确定 FZD6体外促进黑色素瘤细胞侵袭的机制； (2)确定功能意义 FZD6在体内黑色素瘤转移中的作用； (3) 确定临床相关性和治疗意义 FZD6 在黑色素瘤中的作用。拟议的研究具有创新性。我们组建了一支具有多元化专业知识的团队 采取多学科方法，利用功能丧失和获得功能遗传学研究、活细胞成像、诱导 蛋白质降解、基因组学和药物发现。拟议的研究意义重大。我们提出的目标 不仅将揭示 FZD6 介导的 PCP 通路促进黑色素瘤的机制见解 转移，但可作为针对黑色素瘤的药物开发的原理验证研究 管理。由于退伍军人群体患恶性黑色素瘤的风险较高，因此我们的工作是 对我们退伍军人的医疗保健相关且具有重要意义。