Characterization of early events in bulge McSCs and their progeny during melanoma

黑色素瘤期间凸起的 McSC 及其后代的早期事件特征

基本信息

批准号：
8701564
负责人：
Mayumi Ito
金额：
$ 25.43万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8701564
关键词：
Address Adult BRAF gene Behavior Belief Case Study Cells Differentiation and Growth Early Diagnosis Early Intervention Environment Epidermis Event Exposure to Genetic Goals Grant Hair Hair bulb structure Hair follicle structure Harvest Human Immunodeficient Mouse In Situ Incidence Induced Mutation Injury Lead Life Location Malignant - descriptor Methods Modeling Molecular Mus Mutate Mutation Natural regeneration Oncogenic PTEN gene Population Precancerous melanosis Prevention Probability Reporter Risk Factors Sampling Scientist Skin Source Staging Stem cells Techniques Testing Time Tissues Transplantation Tumor Suppressor Proteins Ultraviolet B Radiation Ultraviolet Rays United States Work effective therapy in vivo insight irradiation melanocyte melanoma migration mouse model new therapeutic target novel strategies prevent public health relevance research study tool tumor tumorigenic ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): The goal of this grant is to investigate the melanoma-forming potential of melanocyte stem cells (McSCs) and their progeny, thereby understanding initial events of melanomagenesis. The incidence of melanoma is increasing in the United States, presumably due to increased skin exposure to UV radiation. Currently, there is no way to cure melanoma when it becomes metastatic. Developing targets for early intervention and effective strategies for early diagnosis and prevention are necessary, however the mechanism involved in melanoma initiation is elusive. In mouse melanoma models, we can induce oncogenic mutations in melanocytes. However, melanocytes in mice primarily reside within the hair follicle and their behavior alters during the hair cycle, making it difficult to distinguish te changes caused by oncogenic mutations. Currently, no study has addressed when and how these oncogenic mutations exert its effect on melanocytes in vivo. Despite the belief that stem cells may be the best candidate for the cell of origin in tumors, the involvement of McSCs in melanoma remains unknown. Since McSCs are located in the hair follicle and their primary function is to generate hair melanocytes whereas most melanomas arise from inter-follicular epidermis, this population has been under-studied in melanoma studies. We found that follicular McSCs give rise to epidermal melanocytes in adult mice following UVB-radiation. We hypothesize that McSCs in the bulge may be the origin of epidermal melanocytes that are responsible for melanoma. In Aim 1, we will use genetic mouse models to induce oncogenic mutations (BRAF activation and PTEN loss that are often found in human melanoma) in McSCs. We will also utilize a genetically tractable fluorescent reporter to trace the fate and behavior of the mutated melanocyte. Utilizing these mice, we will carefully delineate how mutations induce change in proliferation, differentiation and migration status of melanocytes in the bulge and epidermis at each stage of the hair follicle cycle. These analyses will be the first to capture the initial alterations in melanocytes driven by oncogenic mutations and to determine the incidence of melanomagenesis from distinct populations of melanocytes. In Aim 2, we will isolate the melanocytes from distinct locations to examine their potential to produce melanoma upon transplantation and induction of the mutations in immunodeficient mice. By analyzing the incidence of melanoma in each specific population, we will determine whether there are intrinsic differences that cause melanoma formation. Elucidating the cell of origin through these in situ and ex vivo studies will ultimately help identification of novel strategies to prevent melanomagenesis.

描述（由申请人提供）：这项资助的目标是研究黑色素细胞干细胞（McSC）及其后代的黑色素瘤形成潜力，从而了解黑色素瘤发生的初始事件。在美国，黑色素瘤的发病率正在增加，可能是由于皮肤暴露于紫外线辐射的增加。目前，当黑色素瘤发生转移时，还没有办法治愈它。有必要制定早期干预目标以及早期诊断和预防的有效策略，但黑色素瘤发生的机制尚不清楚。在小鼠黑色素瘤模型中，我们可以诱导黑色素细胞的致癌突变。然而，小鼠的黑素细胞主要驻留在毛囊内，它们的行为在毛发周期中发生变化，因此很难区分致癌突变引起的变化。目前，还没有研究探讨这些致癌突变何时以及如何对体内黑素细胞产生影响。尽管人们相信干细胞可能是肿瘤起源细胞的最佳候选者，但 McSC 在黑色素瘤中的作用仍然未知。由于 McSC 位于毛囊中，其主要功能是生成毛发黑色素细胞，而大多数黑色素瘤源自毛囊间表皮，因此黑色素瘤研究中对该群体的研究还不够。我们发现，在 UVB 辐射后，成年小鼠的毛囊 McSC 会产生表皮黑素细胞。我们假设凸起中的 McSC 可能是导致黑色素瘤的表皮黑色素细胞的起源。在目标 1 中，我们将使用遗传小鼠模型在 McSC 中诱导致癌突变（BRAF 激活和 PTEN 缺失，常见于人类黑色素瘤）。我们还将利用基因上易于处理的荧光报告基因来追踪生物的命运和行为突变的黑素细胞。利用这些小鼠，我们将仔细描绘突变如何在毛囊周期的每个阶段引起凸起和表皮中黑素细胞的增殖、分化和迁移状态的变化。这些分析将首先捕捉到由致癌突变驱动的黑素细胞的初始改变，并确定不同黑素细胞群体的黑素瘤发生率。在目标 2 中，我们将从不同位置分离黑素细胞，以检查其在免疫缺陷小鼠中移植和诱导突变后产生黑色素瘤的潜力。通过分析每个特定人群中黑色素瘤的发病率，我们将确定是否存在导致黑色素瘤形成的内在差异。通过这些原位和离体研究阐明细胞起源将最终有助于确定预防黑色素瘤生成的新策略。