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: 10560473
• 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/10560473
• 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; Genes; Genetic study; Genomics; Goals; Healthcare; Human; In Vitro; Invaded; Iraq; Knock-out; Lung; Lysosomes; MEKs; Malignant Neoplasms; Matrix Metalloproteinases; 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; 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; Tumor Promotion; United States Department of Veterans Affairs; Veterans; Work; 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; loss of function; 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 只有大约1%的皮肤癌，但它是皮肤癌死亡的主要原因。美国军方人员已向 由于在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。 根据退伍军人事务部中央癌症登记处，黑色素瘤是五个最常见的诊断之一 VA癌症患者中的癌症。美国退伍军人将继续容易受到黑色素瘤，因为美国军队 目前正在和最近一直在几个高紫外线（UV）指数区执行任务，如伊拉克 和阿富汗因此，迫切需要设计减缓黑色素瘤进展的策略，从而导致黑色素瘤的发生。 长期甚至永久存活的患者。目前在黑色素瘤研究方面的努力很大程度上 专注于阻断细胞增殖或杀死肿瘤细胞。然而，也有可能治疗这种疾病 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， 到组织轴。越来越多的证据表明，它也通过促进肿瘤细胞增殖而在癌症中发挥作用。 移民和入侵。虽然有一些关于某些癌症中PCP途径的信息， 其在黑色素瘤中的作用尚未研究。我们研究的长期目标是剖析 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， 发现卷曲蛋白6（FZD 6），核心PCP基因之一，在多种黑素瘤细胞系中过表达， 人体组织FZD 6的敲低（KD）或敲除（KO）不影响细胞增殖，但显著影响细胞增殖。 降低黑色素瘤细胞的侵袭能力。此外，我们发现Fzd 6的KO显著降低了 在黑色素瘤Pten/BRaf小鼠模型中的肺转移。因此，我们假设FZD 6促进了 黑色素瘤的侵袭和转移通过调节细胞极性，并可作为新的目标， 黑色素瘤管理。我们将以以下三个目标来检验这一假设：（1）确定 FZD 6促进黑色素瘤细胞体外侵袭的机制;（2）确定功能意义 FZD 6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 FZD 6在黑素瘤中的作用该研究具有创新性。我们组建了一个拥有各种专业知识的团队 采取多学科的方法，使用功能丧失和获得的遗传研究，活细胞成像，诱导 蛋白质降解、基因组学和药物发现。所提出的研究是有意义的。我们提出的目标 不仅揭示了FZD 6介导的PCP途径在促进黑色素瘤中的机制见解， 转移，但作为药物开发的原理验证研究，以靶向该系统治疗黑色素瘤 管理由于退伍军人群体患恶性黑色素瘤的风险较高，我们的工作是 对我们退伍军人的医疗保健至关重要。