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略性的癌症，始于皮肤中的黑色素黑色素细胞。它的帐户 仅大约1％的皮肤癌，但这是皮肤癌死亡的主要原因。美国军事人员有 由于在部署环境中暴露于阳光的情况下，黑色素瘤的比率高于平民。 根据退伍军人事务中央癌症注册表，黑色素瘤是最常诊断的五个 VA癌症患者中的癌症。作为美国军方，美国退伍军人将继续容易患黑色素瘤 目前曾经并且最近在几个高紫外线（UV）指数区从事任务，例如伊拉克 和阿富汗。因此，迫切需要制定策略来减缓黑色素瘤的发展，导致 退伍军人患者的延长甚至永久生存。当前在黑色素瘤研究方面的努力很大 专注于阻断细胞增殖或杀死肿瘤细胞。但是，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的发育过程中极性 到组织轴。越来越多的证据表明，它也通过促进肿瘤细胞在癌症中起作用 迁移和入侵。尽管有一些有关某些癌症的PCP途径的信息，但 尚未研究其参与黑色素瘤。我们研究的长期目标是剖析角色和 PCP途径在黑色素瘤发育和进展中的机制。在我们的初步研究中，我们有 发现核心PCP基因之一的毛躁6（FZD6）在多个黑色素瘤细胞系中过表达，并且 人体组织。 FZD6的敲低（KD）或淘汰（KO）不影响细胞的增殖，但显着 降低了黑色素瘤细胞的侵入性能力。此外，我们发现FZD6的KO大幅减少 黑色素瘤PTEN/BRAF小鼠模型中的肺转移。因此，我们假设FZD6促进 通过调节细胞极性，黑色素瘤侵袭和转移可以作为新的目标 黑色素瘤管理。我们将以以下三个目的检验该假设：（1）确定 FZD6在体外促进黑色素瘤细胞侵袭中的机制； （2）确定功能意义 在体内黑色素瘤转移中的Fzd6; （3）确定临床相关性和治疗意义 黑色素瘤中的FZD6。拟议的研究是创新的。我们已经组建了一个具有多样专业知识的团队 使用功能障碍和功能遗传学研究，实时成像，可诱导的损失和功能获得的多学科方法 蛋白质降解，基因组学和药物发现。拟议的研究很重要。我们提出的目标 不仅将在促进黑色素瘤中推出FZD6介导的PCP途径的机械见解 转移，但作为药物开发的原则研究证明，以靶向该系统用于黑色素瘤 管理。由于资深人口患恶性黑色素瘤的风险更高，我们的工作是 与我们的退伍军人的医疗保健相关且重要。