Mechanisms of melanoma migration and survival in 3D microenvironments

3D 微环境中黑色素瘤迁移和存活的机制

基本信息

批准号：
9883752
负责人：
Erik S Welf
金额：
$ 11.61万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9883752
关键词：
1-Phosphatidylinositol 3-Kinase 3-Dimensional Actins Actomyosin Affect Binding Binding Proteins Biological Bulla CD44 gene Cell Survival Cell physiology Cell surface Clustered Regularly Interspaced Short Palindromic Repeats Collagen Fiber Complement Computer Analysis Computer Models Data Diglycerides Encapsulated Equilibrium Exhibits Extracellular Matrix Family Family member Image In Vitro Laboratories Measures Mediating Melanoma Cell Membrane Mentorship Metastatic Melanoma Metastatic to Molecular Molecular Conformation Mus Mutation Neoplasm Metastasis Neural Crest Cell Pathway interactions Patients Phosphatidylinositol 4,5-Diphosphate Phospholipids Phosphorylation Prevalence Process Property Protein Family Proteins Research Personnel Role Sampling Shapes Signal Transduction Structure Structure of primordial sex cell Surface Testing Threonine Tissues Training Training Activity Xenograft Model Zebrafish advanced disease cell motility experience ezrin faculty mentor genome editing in vivo live cell imaging melanoma metastatic process migration moesin mortality neoplastic cell non-Native polymerization pressure public health relevance radixin protein receptor scaffold skills soft tissue spatiotemporal therapy design tumor progression

项目摘要

DESCRIPTION (provided by applicant): A greater understanding of the mechanisms mediating melanoma metastasis is necessary for treatment of advanced disease. Because all melanoma cells must move through and survive in non-native tissue microenvironments during metastatic dissemination, the ability to migrate and survive in these microenvironments is critical for metastatic potential. We and others have observed that melanoma cells encapsulated in 3-dimensional extracellular matrices that mimic soft tissues exhibit spontaneous and continuous non-apoptotic membrane blebbing. These observations have led us to ask if membrane blebbing is associated with the ability to survive and migrate through soft tissues. We propose to study the mechanisms that may enable melanoma migration and survival during metastatic dissemination as a function of membrane blebbing. Thus, the scientific objective of this project is to determine how blebbing is related to metastatic dissemination in melanoma. At the completion of this project, we will have determined if blebbing is enriched in stage III melanoma samples that exhibit efficient metastasis compared to stage III samples that exhibit less efficient metastasis, and we will have determined if these differences in metastatic efficiency are mediated by the scaffolding function of the ERM family protein ezrin. We will have determined if the spatiotemporal organization of phospholipid signaling regulates ezrin phosphorylation to organize membrane blebs that facilitate cell migration in 3D matrices, and we will have determined if membrane blebbing facilitates survival signaling by regulating the spatial partitioning of ezrin between membrane and cytosolic compartments. The training objective of this proposal is to train Dr. Erik Welf in the skills required to become an independent investigato specializing in quantitative approaches to dissect the mechanisms underlying metastatic dissemination of melanoma. The proposed training activities will complement Dr. Welf's previous experience in computational modeling and analysis by providing training in the cutting edge molecular biological, imaging, and in vivo approaches necessary to study the processes of metastatic dissemination in realistic microenvironments. The proposed project leverages the expertise of faculty mentors Gaudenz Danuser and Sean Morrison, who are experts in the fields of live cell imaging and in vivo approaches, respectively. The dynamic interplay between analytical and experimental approaches is fundamental to the approach that Dr. Welf will apply as an independent researcher, and this training experience will complete the skills to facilitate this approach. Although few, if any, existing laboratories can boast expertise in both analytical and experimental approaches relevant to melanoma, the proposed mentorship team will enable Dr. Welf to develop the skills required to become successful in this endeavor.

描述（由适用提供）：对介导黑色素瘤转移的机制有更深入的了解，对于治疗晚期疾病是必要的。由于所有黑色素瘤细胞在转移性传播过程中必须在非本地组织微环境中移动并存活，因此在这些微环境中迁移和生存的能力至关重要我们和其他人观察到，模仿软尖和连续的非凋亡膜爆炸中的三维细胞外属性物质中的黑色素瘤细胞。这些观察结果使我们询问黑色素瘤出现是否与通过软尖端迁移和迁移的能力有关。我们建议研究可能在转移性传播过程中使黑色素瘤迁移和生存的机制作为膜出现的函数。这是该项目的科学目标是确定爆炸与黑色素瘤中转移性传播的关系。该项目完成时，我们将确定是否在暴露于有效转移的第三阶段黑色素瘤样品中，与暴露效率较低的第三阶段样品相比转移，我们将确定转移效率的这些差异是否是由ERM家族蛋白Ezrin的脚手架功能介导的。我们将确定磷脂信号传导的空间临时组织是否调节ezrin磷酸化，以组织膜爆炸，从而促进3D材料中细胞迁移的膜爆炸，我们将确定膜是否通过对膜片综合和Cytosocolocic Comparts之间的空间分化来支持膜支持存活信号。该建议的培训目标是培训Erik Welf博士，以成为专门研究定量方法的独立研究人员所需的技能，以剖析黑色素瘤转移性传播的机制。提出的培训活动将通过在尖端分子生物学，成像和研究现实微环境中转移性传播过程中提供尖端分子生物学，成像和体内方法，以完成沃尔夫博士以前在计算建模和分析方面的经验。拟议的项目分别利用了教师导师高登兹·丹纳瑟（Gaudenz Danuser）和肖恩·莫里森（Sean Morrison）的专业知识，后者分别是实时细胞成像和体内方法领域的专家。分析方法和实验方法之间的动态相互作用是沃尔夫博士作为独立研究人员采用的方法至关重要的，而这种培训经验将完成促进这种方法的技能。尽管很少（如果有的话）现有的实验室可以在与黑色素瘤相关的分析和实验方法方面拥有专业知识，但拟议的Mentalship团队将使Welf博士能够发展在这项努力中取得成功所需的技能。