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.

项目摘要/摘要 黑色素瘤来自表皮基底层中黑色素细胞（MC）的转化 被角质形成细胞（KCS）包围。虽然研究主要集中于识别驾驶员突变 参与MC转化为黑色素瘤，异常KC的组织学正常场也存在 黑色素瘤出现的阳光暴露的表皮。通过改变KC促进黑色素瘤的程度 围绕早期病变是未知的。我们的长期目标是定义KC的改变：MC 沟通驱动黑色素瘤的发育并确定色素nevi周围的KC的变化 作为恶性转化和治疗靶标的预测指标。 KC：MC互动发生 直接通过钙粘蛋白并间接通过分泌的因素。经典钙粘蛋白表达的改变 已知会影响黑色素瘤的起始和进展 在黑色素瘤中。我们的数据支持脱染体钙粘蛋白Desmoglein 1（DSG1）对MC至关重要的想法。 稳态即使仅在邻近的KCS中表达。 DSG1的丢失刺激了生产 KC细胞因子和其他分泌因素，这些因素增加了MC数，树突，色素产生和促值 肿瘤性细胞因子表达。这些功能类似于MC对紫外线（UV）光的响应，我们 表明紫外线会导致KC DSG1的选择性丢失。我们的数据还表明，DSG1被分泌抑制 黑色素瘤细胞的因素及其表达在人类周围的巢中降低 黑色素瘤和发育不良的NEVI。这表明存在稳定DSG1缺陷的反馈回路 亲素金素KC：肿瘤微环境中的MC单位。我们建议DSG1在UV之后的损失 暴露有助于MC对紫外线的反应，但长期损害和长期抑制DSG1 通过协调促肿瘤旁分泌信号传导来促进黑色素瘤的发育 KC：MC联系。我们将使用候选人和对DSG1缺陷2/3D人类模型的无偏分析，人类 组织和新型CRISPR/CAS DSG1缺陷小鼠模型与HGF动物模型结合 与人类病理相似的黑色素瘤与：1）确定DSG1损失如何改变KC分泌组 并通过合作旁分泌和细胞接触刺激类似UV反应的MC行为 依赖信号和2）确定如何建立持续的DSG1缺陷KC：MC单元以促进 恶性转化和黑色素瘤发育。了解KC：MC通信将提供 开发新生物标志物的基础，以识别患有恶性黑色素瘤的高风险的个体， 谁可能是与恢复正常KC：MC通信的药物进行预防治疗的候选者。