Investigating the epidermal microenvironment in melanoblast migration and invasion: a novel approach to understanding invasive melanoma

研究黑色素细胞迁移和侵袭的表皮微环境：一种了解侵袭性黑色素瘤的新方法

• 批准号: 10537221
• 负责人: Denay Richards
• 金额: $ 5.18万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537221
• 关键词: Actins; Adherens Junction; Adhesions; Adhesives; Basement membrane; Basic Science; Behavior; Belief; Biological; Cadherins; Cells; Cellular biology; Cessation of life; Clinical; Collaborations; Color; Complex; Cre lox recombination system; Data; Defect; Development; Diagnosis; Disease; E-Cadherin; Embryo; Environment; Epidermis; Epithelial; Epithelial Cells; Esthetics; Excision; Fibroblasts; Future; Genetic; Genetic Transcription; Goals; Hair follicle structure; Homeostasis; Hospital Departments; Human; Image; Immune; Immunoglobulin Class Switching; Impairment; Incidence; Individual; Intercellular Junctions; Intervention; Keloid; Knock-out; Knowledge; Label; Life; Mechanics; Medical; Melanoma Cell; Membrane; Mentorship; Metastatic Melanoma; Metastatic to; Microscopy; Molecular; Morphology; Mus; N-Cadherin; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Pigments; Plastic Surgeon; Plastic Surgical Procedures; Precancerous melanosis; Recording of previous events; Reporter; Research; Resolution; Resources; Role; Skin; Skin Cancer; Surgeon; Survival Rate; Testing; Therapeutic Human Experimentation; Training; Translational Research; Tumor Suppression; United States; Universities; University Hospitals; Up-Regulation; Vitiligo; Wood material; Work; base; cell motility; cell type; cellular imaging; confocal imaging; design; holistic approach; intercellular communication; keratinocyte; melanoblast; melanocyte; melanoma; migration; mortality; mouse model; novel strategies; prevent; promoter; reconstruction; skin barrier; transcriptomics; tumor

Melanoma, while composing only 1% of all skin cancers, causes the majority of skin cancer related deaths. In the United States alone, over 100,000 new patients have been diagnosed with melanoma in 2021. While plastic surgeons are frequently responsible for the oncologic reconstruction and removal of melanoma, few surgeons in this field have the basic science training needed to understand the underlying molecular defects of this condition or the dynamics of the mammalian epidermal microenvironment, in which they specialize. Such knowledge is crucial for a holistic approach to the field of plastic surgery because the dysregulation of intercellular communication between cells in this skin microenvironment, such as melanocytes, fibroblasts, and keratinocytes, leads to various aesthetic and life altering defects such as those seen in vitiligo, keloid formation and melanoma. We believe that a better understanding of developmental melanoblast migration can provide a framework for future patient interventions and provide much needed context for future surgeons. This belief is supported by recent studies in human melanoma, which show that the transcriptomic genetic profile of melanoma cells closely mimic developmental melanoblasts. Second, it is well established that one of the hallmarks of malignant melanoma is the loss of E-cadherin and upregulation of N-cadherin, but how adhesive interactions between melanocytes and their surrounding keratinocytes via E-cadherin regulate melanocyte behavior and homeostasis is not well understood. I hypothesize that melanocytes form specialized adhesions with keratinocytes that serve to maintain the epidermal barrier while simultaneously promoting melanocyte migration, colonization, and retention within the epidermis. I plan to test this hypothesis, by using the Cre-Lox system under the control of a K14 epithelial promoter to selectively label melanocytes and knockout E-cadherin in the keratinocyte microenvironment of the epidermis. I will then characterize the impact of disrupted melanocyte-epithelial adhesions on melanocyte migration, protrusivity and colonization (Aim 1), identify the composition and localization of melanocyte-epidermal adhesions and actin regulators (Aim 2) and determine the impact of disrupted melanocyte-epithelial AJs on melanoma progression in a melanoma mouse model (Aim 3). This proposed project will be the first of its kind to characterize the impact of the surrounding keratinocyte microenvironment on melanoblast migration and function; thus, seeing the epidermis as a complex microenvironment with varying cell types, a biological reality that is often overlooked in medical training. This proposed project and the training plan herein is designed to cultivate the necessary training to provide an increase in translational research to the field of plastic surgery. This collaboration between Princeton University and Robert Wood Johnson University Hospital Department of Plastic Surgery provides the clinical, basic science training, mentorship, and resources necessary to accomplish this goal. It is our hope that this work will be used to benefit patients with a history of melanoma worldwide.

黑色素瘤虽然只占所有皮肤癌的1％，但会导致大多数与皮肤癌相关的死亡。在 仅美国，超过100,000名新患者在2021年被诊断出患有黑色素瘤。 整形外科医生经常负责肿瘤学重建和去除黑色素瘤，很少 该领域的外科医生具有了解理解基础科学培训的基础训练 这种情况或哺乳动物表皮微环境的动力学，它们在其中专门化。这样的 知识对于整体手术领域至关重要，因为 这种皮肤微环境中细胞之间的细胞间通信，例如黑素细胞，成纤维细胞和 角质形成细胞，导致各种审美和生活改变缺陷，例如在白紫虫中看到的缺陷 和黑色素瘤。我们认为，更好地了解发育性黑素细胞迁移可以提供 未来患者干预措施的框架，并为未来的外科医生提供急需的环境。这种信念是 在人类黑色素瘤最近的研究中支持，这些研究表明 黑色素瘤细胞紧密模仿发育性黑色素细胞。其次，一个很好的证明是 恶性黑色素瘤的标志是E-钙粘蛋白的丧失和N-钙粘蛋白的上调，但如何粘合剂 黑素细胞与周围角质形成细胞之间的相互作用通过E-钙粘蛋白调节黑素细胞 行为和体内平衡并不理解。我假设黑素细胞形成专业粘附 与角质形成细胞一起维持表皮屏障的同时促进黑素细胞 表皮内的迁移，定殖和保留。我计划通过使用Cre-lox检验这一假设 在K14上皮启动子控制下的系统，可有选择地标记黑色素细胞和基因敲除电子蛋白 在表皮的角质形成细胞微环境中。然后，我将描述中断的影响 黑素细胞上皮粘附在黑素细胞迁移，脉冲和定殖（AIM 1）上，鉴定 黑素细胞 - 表皮粘附和肌动蛋白调节剂的组成和定位（AIM 2）并确定 黑色素瘤小鼠模型中黑色素细胞上皮AJS对黑色素瘤进展的影响（AIM） 3）。这个提议的项目将是表征周围角质形成细胞影响的第一个此类项目 在黑素细胞迁移和功能上的微环境；因此，将表皮视为复杂 具有不同细胞类型的微环境，这是一种生物学现实，在医学训练中经常被忽略。这 拟议的项目和本文培训计划旨在培养必要的培训，以提供 增加对整形外科领域的翻译研究。普林斯顿大学之间的合作 罗伯特·伍德·约翰逊大学（Robert Wood Johnson University）整形外科系提供了临床，基本 实现这一目标所需的科学培训，指导和资源。我们希望这项工作会 被用来使全球黑色素瘤病史的患者受益。