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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

基本信息

批准号：
10337049
负责人：
Kathleen Janee Green
金额：
$ 38.62万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10337049
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

项目摘要

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/文摘