Role of Desmoglein 1 in Keratinocyte-Melanocyte Communication and Melanoma

桥粒芯糖蛋白 1 在角质细胞-黑色素细胞通讯和黑色素瘤中的作用

• 批准号: 10092121
• 负责人: Kathleen Janee Green
• 金额: $ 39.92万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092121
• 关键词: 3-Dimensional; Abnormal Keratinocyte; Affect; Animal Model; Antioxidants; Attenuated; Behavior; Binding; Biological Markers; Cadherins; Cell Adhesion Molecules; Cell-Cell Adhesion; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Communication; Data; Development; Down-Regulation; Dysplastic Nevus; ERBB2 gene; Epidermis; Exhibits; Feedback; Genetic; Histologic; Homeostasis; Human; Human Pathology; Individual; Knowledge; Lesion; Malignant - descriptor; Malignant Neoplasms; Melanocytic nevus; Melanogenesis; Melanoma Cell; Modeling; Movement; N-Cadherin; Paracrine Communication; Pigments; Play; Production; Prophylactic treatment; Proteins; Research; Role; Signal Transduction; Skin Cancer; Skin Carcinoma; Skin tanning; Stratum Basale; Sun Exposure; Testing; UV Radiation Exposure; UV response; Ultraviolet Rays; biological adaptation to stress; cell type; cytokine; desmoglein 1; driver mutation; high risk; human model; human tissue; keratinocyte; melanocyte; melanoma; melanomagenesis; mouse model; mutant; novel; paracrine; peroxiredoxin I; response; scaffold; therapeutic target; three-dimensional modeling; tumor microenvironment; tumorigenic; ultraviolet

Project Summary/Abstract Melanoma arises from transformation of melanocytes (MCs) in the basal layer of the epidermis where they are surrounded by keratinocytes (KCs). While research has focused predominantly on identifying driver mutations involved in conversion of MCs to melanoma, histologically normal fields of abnormal KCs are also present in sun-exposed epidermis in which melanomas arise. The extent to which melanoma is promoted by altered KCs that surround early lesions is unknown. Our long-term objectives are to define how altered KC:MC communication drives melanoma development and to identify alterations in KCs surrounding pigmented nevi that serve as predictors of malignant transformation and as therapeutic targets. KC:MC interactions occur directly through cadherins and indirectly through secreted factors. Alterations in classic cadherin expression are known to affect melanoma initiation and progression, but little is known about desmosomal cadherins' roles in melanoma. Our data support the idea that the desmosomal cadherin, desmoglein 1 (Dsg1), is critical for MC homeostasis even though it is expressed only in neighboring KCs. Loss of Dsg1 stimulates the production of KC cytokines and other secreted factors that increase MC number, dendricity, pigment production, and pro- tumorigenic cytokine expression. These features resemble the MC response to ultraviolet (UV) light, and we showed that UV results in selective loss of KC Dsg1. Our data also show that Dsg1 is suppressed by secreted factors from melanoma cells, and its expression is decreased in peri-lesional nests surrounding human melanomas and dysplastic nevi. This suggests the existence of a feedback loop that stabilizes a Dsg1-deficient pro-melanomagenic KC:MC unit within the tumor microenvironment. We propose that Dsg1's loss following UV exposure contributes to MC responses to UV, but that chronic damage and prolonged suppression of Dsg1 promotes melanoma development through coordination of pro-tumorigenic paracrine signaling and altered KC:MC contact. We will use candidate and unbiased analysis of Dsg1-deficient 2/3D human models, human tissues and a novel CRISPR/Cas Dsg1-deficient mouse model in conjunction with an HGF animal model of melanoma that closely resembles human pathology to: 1) Determine how Dsg1 loss alters the KC secretome and stimulates MC behaviors resembling the UV response through cooperative paracrine and cell contact- dependent signaling and 2) Determine how a sustained Dsg1-deficient KC:MC unit is established to promote malignant transformation and melanoma development. Understanding KC:MC communication will provide the basis for development of new biomarkers to identify individuals at high risk of developing malignant melanoma, and who may be candidates for prophylactic treatment with agents that restore normal KC:MC communication.

项目总结/摘要 黑色素瘤由表皮基底层中的黑色素细胞（MC）转化而产生， 被角质形成细胞（KCs）包围。虽然研究主要集中在识别驱动突变 参与MC向黑色素瘤的转化，异常KC的组织学正常区域也存在于 黑色素瘤生长的暴露于阳光下的表皮。改变的KC促进黑色素瘤的程度 早期病变周围的组织是未知的。我们的长期目标是确定如何改变KC：MC 通信驱动黑色素瘤的发展，并确定色素痣周围KCs的改变 作为恶性转化的预测因子和治疗靶点。KC：MC相互作用发生 直接通过钙粘蛋白和间接通过分泌因子。经典钙粘蛋白表达的改变 已知影响黑色素瘤的发生和发展，但对桥粒钙粘蛋白的作用知之甚少 黑色素瘤我们的数据支持桥粒钙粘蛋白，桥粒芯糖蛋白1（Dsg 1），是MC的关键， 即使它只在邻近的KC中表达，也能保持体内平衡。Dsg 1的缺失刺激了 KC细胞因子和其他分泌因子增加MC数量、树突状细胞、色素产生和促增殖。 致瘤细胞因子表达。这些特征类似于MC对紫外线（UV）光的响应， 结果表明，紫外线导致KC Dsg 1的选择性丧失。我们的数据还表明，Dsg 1被分泌型 因子，并且其表达在人类周围的病灶巢中降低 黑色素瘤和发育不良痣。这表明存在一个反馈回路，可以稳定Dsg 1缺陷的细胞。 肿瘤微环境内的促黑素原KC：MC单位。我们认为Dsg 1在紫外光照射后的损失 暴露有助于MC对UV的反应，但慢性损伤和Dsg 1的长期抑制 促进黑色素瘤的发展，通过协调促肿瘤旁分泌信号和改变 KC：MC联系。我们将使用Dsg 1缺陷2/3D人体模型的候选和无偏分析， 组织和一种新的CRISPR/Cas Dsg 1缺陷型小鼠模型与HGF动物模型联合， 与人类病理学非常相似的黑色素瘤：1）确定Dsg 1缺失如何改变KC分泌组 并通过协同的旁分泌和细胞接触刺激类似于UV反应的MC行为- 2）确定持续的Dsg 1缺陷KC：MC单位是如何建立的，以促进 恶性转化和黑色素瘤发展。了解KC：MC沟通将提供 开发新的生物标志物以鉴定处于发展恶性黑色素瘤的高风险的个体的基础， 并且可能是用恢复正常KC：MC通讯的药剂进行预防性治疗的候选者。