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）：该赠款的目的是研究黑素细胞干细胞（MCSC）及其后代的黑色素瘤形成潜力，从而了解黑色素瘤的初始事件。在美国，黑色素瘤的发生率正在增加，大概是由于皮肤暴露于紫外线辐射。当前，当变化时，无法治愈黑色素瘤。为了开发早期干预的目标和有效的早期诊断和预防策略是必要的，但是涉及黑色素瘤起始的机制是难以捉摸的。在小鼠黑色素瘤模型中，我们可以在黑素细胞中诱导致癌突变。然而，小鼠的黑素细胞主要居住在毛囊中及其在头发周期中的行为改变，因此很难区分由致癌突变引起的TE变化。目前，尚未解决这些致癌突变何时以及如何对体内黑色素细胞发挥作用。尽管认为干细胞可能是肿瘤起源细胞的最佳候选者，但MCSC在黑色素瘤中的参与仍然未知。由于MCSC位于毛囊中，其主要功能是产生黑素细胞，而大多数黑色素瘤源自粉状表皮间，因此在黑色素瘤研究中，这种种群不足以研究。我们发现，UVB辐射后，卵泡MCSC在成年小鼠中产生表皮黑素细胞。我们假设凸起中的MCSC可能是导致黑色素瘤的表皮黑素细胞的起源。在AIM 1中，我们将使用遗传小鼠模型诱导MCSC中的致癌突变（BRAF激活和PTEN损失）。我们还将利用遗传上的荧光报道来追踪命运和行为突变的黑素细胞。利用这些小鼠，我们将仔细描述突变如何在毛囊循环的每个阶段凸出的黑素细胞和表皮中的黑素细胞的增殖，分化和迁移状态变化。这些分析将是第一个捕获由致癌突变驱动的黑素细胞的最初改变，并确定黑色素群体群体的黑色素作发生率。在AIM 2中，我们将将黑素细胞与不同位置分离，以检查它们在移植和诱导免疫缺陷小鼠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生率，我们将确定是否存在引起黑色素瘤形成的内在差异。通过这些原位和离体研究阐明原产细胞的细胞最终将有助于鉴定预防黑色素作用的新型策略。