Role of Desmoglein 1 in Keratinocyte-Melanocyte Communication and Melanoma

项目摘要/摘要 黑色素瘤是由表皮基底层的黑素细胞转化而来的。 周围是角质形成细胞(KCs)。虽然研究主要集中在识别驱动程序突变上 参与MC向黑色素瘤的转化，在组织学上正常的异常KCs也出现在 有黑色素瘤的暴露在阳光下的表皮。改变的KCs促进黑色素瘤的程度 早期病变周围的情况尚不清楚。我们的长期目标是定义KC：MC如何改变 沟通推动黑色素瘤的发展，并确定色素痣周围的KCs的变化 作为恶变的预测指标和治疗靶点。KC：发生MC交互作用 直接通过钙粘附素和间接通过分泌因子。经典钙粘附素表达的改变 已知影响黑色素瘤的发生和发展，但对桥粒钙粘附素的作用知之甚少。 死于黑色素瘤。我们的数据支持桥粒钙粘附素1(DSG1)在MC中起关键作用的观点 动态平衡，即使它只在邻近的KC中表达。DSG1的缺失刺激血管生成 KC细胞因子和其他分泌因子可增加MC数量、树突状细胞数、色素产生和促红细胞生成素。 致癌细胞因子的表达。这些特征类似于MC对紫外线(UV)的反应，我们 结果表明，紫外线导致KC-DSG1的选择性丢失。我们的数据还表明，DSG1受到分泌的抑制 来自黑色素瘤细胞的因子，其在人类周围皮损巢中的表达减少 黑色素瘤和发育不良痣。这表明存在稳定DSG1缺陷的反馈环 促黑色素瘤生成KC：肿瘤微环境中的MC单位。我们认为紫外线照射后DSG1的S损失 暴露有助于MC对紫外线的反应，但这种慢性损伤和对DSG1的长期抑制 促进黑色素瘤的发展通过协调促肿瘤的旁分泌信号和改变 KC：MC联系人。我们将对DSG1缺失的2/3D人体模型进行候选和无偏见的分析 组织和一种新的CRISPR/Cas DSG1缺陷小鼠模型和HGF动物模型 与人类病理非常相似的黑色素瘤：1)确定DSG1缺失如何改变KC分泌组 并通过合作旁分泌和细胞接触刺激MC类似UV反应的行为- 依赖的信号转导和2)确定如何建立持续的DSG1缺乏的KC：MC单位来促进 恶性转化和黑色素瘤的发展。了解KC：MC沟通将提供 开发新的生物标记物以识别患恶性黑色素瘤的高危个体的基础， 谁可能是预防性治疗的候选药物，恢复正常的KC：MC通讯。

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.