Understanding PPARgamma signaling in melanoma brain metastasis

了解黑色素瘤脑转移中的 PPARgamma 信号传导

基本信息

批准号：
10534117
负责人：
Qing Chen
金额：
$ 39.93万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10534117
关键词：
Address Agonist Apoptosis Arachidonic Acids Astrocytes Binding Biological Assay Brain Cancer Patient Cells Cephalic Cessation of life Clinic Clinical Coculture Techniques Coin Complex Data Disseminated Malignant Neoplasm Distal E-Cadherin Epithelium Experimental Models Fatty Acids Fatty acid glycerol esters Gene Expression Profiling Genes Genetic Goals Growth In Vitro Incidence Individual Invaded Kinetics Location Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Mediator Melanoma Cell Mesenchymal Metastatic Melanoma Metastatic malignant neoplasm to brain Modeling Neoplasm Metastasis Neuroglia Neurons Oleic Acids Organ PPAR gamma Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phenotype Primary Neoplasm Process Production Proliferating Recurrent Malignant Neoplasm Relapse Reporter Research Response Elements Role Sampling Signal Transduction Site Soil Stains Stromal Cells Systemic Therapy Techniques Testing Time Unsaturated Fatty Acids Xenograft procedure aldehyde dehydrogenases antagonist astrogliosis beta catenin brain cell cancer cell cancer recurrence cell motility cell type design effective therapy experimental study in vitro Model in vivo insight intravital microscopy melanoma metastatic process migration mouse model novel novel therapeutic intervention pharmacologic pre-clinical promoter receptor small molecule inhibitor spatiotemporal therapeutic target therapy resistant

项目摘要

Project Summary Metastasis, the spread of cancer from primary tumor site to distal organs, is the cause of over 80% of deaths from cancer. The brain is one of the common metastasis locations. Brain metastasis, which develops in the late course of illness, has become a significant problem in clinic due to its rising incidence as a consequence of prolonged survival and limited efficacy of existing systemic therapies. Metastasis is a multi-step process that requires the complex interplay between cancer cells and the stromal cells, a process commonly referred to as “seed and soil hypothesis” coined over a century ago. The ‘soil’, the microenvironment, not only decides the outgrowth of metastatic cancer cells, but also contributes to therapy resistance. The ‘seed’, the invaded cancer cells, directly modifies the surrounding brain stromal cells. Our long-term goal is to dissect the complex interactions between cancer cells and brain stromal cells during metastasis. We have developed novel in vivo and in vitro models to address the gaps in our understanding of brain microenvironmental control of metastatic outgrowth. Our data implicate that astrocytes, the unique and most abundant brain cells, activate PPARγ signaling in brain metastatic melanoma cells. Through an integrative approach using in vitro co-culture assays and in vivo brain metastatic mouse models, Aim 1 will delineate the role of PPARγ pathway in melanoma cells during brain metastasis. We will track the dynamic changes and effect of PPARγ signaling in melanoma cells throughout the whole brain metastatic process. Moreover, PPARγ antagonist will be used in our pre-clinical mouse models to test its potential to treat melanoma brain metastasis. Aim 2 will address how astrocytes activate PPARγ signaling in the invades melanoma cells. We hypothesize that astrocytes serve as ‘donor’ of unsaturated fatty acids, natural agonist of PPARγ, to the invaded melanoma cells. The gained insights may enable us to mechanistically deconstruct melanoma brain metastasis and develop new treatment strategies for patients with little clinical recourse.

项目概要转移，即癌症从原发肿瘤部位扩散到远端器官，是 80% 以上死亡的原因脑部是癌症常见的转移部位之一。由于其发病率不断上升，已成为临床上的一个重要问题现有全身疗法的延长生存期和有限疗效是一个多步骤的过程。需要癌细胞和基质细胞之间复杂的相互作用，这个过程通常被称为一个多世纪前提出的“种子和土壤假说”，“土壤”，即微环境，不仅决定了种子的生长。转移性癌细胞的生长，但也会导致治疗耐药性，即“种子”，即侵袭性癌症。细胞，直接修改周围的脑基质细胞，我们的长期目标是解剖复杂的细胞。转移过程中癌细胞与脑基质细胞之间的相互作用。我们开发了新颖的体内和体外模型来解决我们对大脑理解的空白我们的数据表明星形胶质细胞是最独特且最重要的微环境控制。丰富的脑细胞，通过整合激活脑转移性黑色素瘤细胞中的 PPARγ 信号传导。使用体外共培养测定和体内脑转移小鼠模型的方法，目标 1 将描绘我们将追踪PPARγ通路在黑色素瘤细胞脑转移过程中的动态变化和作用。整个脑转移过程中黑色素瘤细胞中 PPARγ 信号传导的研究。拮抗剂将用于我们的临床前小鼠模型，以测试其治疗黑色素瘤脑转移的潜力。目标 2 将解决星形胶质细胞如何激活侵入黑色素瘤细胞中的 PPARγ 信号传导。星形胶质细胞充当不饱和脂肪酸（PPARγ 的天然激动剂）向侵入的黑色素瘤的“供体” 所获得的见解可能使我们能够机械地解构黑色素瘤脑转移并发展。针对临床资源匮乏的患者的新治疗策略。