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%，但却导致了大多数皮肤癌相关死亡。在 仅在美国，2021年就有超过10万名新患者被诊断患有黑色素瘤。而 整形外科医生通常负责肿瘤重建和黑色素瘤的切除， 这一领域的外科医生接受过基本的科学培训，以了解潜在的分子缺陷。 这种情况或哺乳动物表皮微环境的动态，他们专门。等 知识对于整形外科领域的整体方法至关重要，因为 在这种皮肤微环境中的细胞之间的细胞间通讯，例如黑素细胞、成纤维细胞和 角质形成细胞，导致各种美学和改变生活的缺陷，如白癜风，瘢痕疙瘩形成中所见的那些 和黑色素瘤我们相信，更好地了解发育中的黑素细胞迁移可以提供一个 未来患者干预的框架，并为未来的外科医生提供急需的背景。这种信念是 最近在人类黑色素瘤中的研究支持了这一点，这些研究表明， 黑色素瘤细胞与发育中的成黑色素细胞非常相似。第二，众所周知， 恶性黑色素瘤的标志是E-cadherin的丢失和N-cadherin的上调，但如何粘附 黑素细胞与其周围角质形成细胞之间相互作用通过E-cadherin调节黑素细胞 行为和体内平衡还没有很好的理解。我假设黑色素细胞形成了专门的粘连 角质细胞用于维持表皮屏障，同时促进黑素细胞 迁移、定殖和保留在表皮内。我打算用Cre-Lox来验证这个假设 在K14上皮启动子控制下选择性标记黑素细胞并敲除E-钙粘蛋白的系统 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-上皮细胞粘连对黑素细胞迁移、增殖和定植的影响（目的1），确定 黑素细胞-表皮粘附和肌动蛋白调节因子的组成和定位（目的2），并确定 在黑色素瘤小鼠模型中，破坏的黑色素细胞-上皮AJs对黑色素瘤进展的影响（Aim 3）。这个拟议的项目将是第一个同类的特点，周围角质细胞的影响， 微环境对成黑色素细胞迁移和功能的影响;因此，将表皮视为一个复杂的 微环境与不同的细胞类型，一个生物学的现实，往往被忽视的医疗培训。这 建议的项目和培训计划旨在培养必要的培训， 增加整形外科领域的转化研究。普林斯顿大学和 和罗伯特伍德约翰逊大学医院整形外科部提供的临床，基本 科学培训、指导和实现这一目标所需的资源。我们希望这项工作将 用于全球有黑色素瘤病史的患者。