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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：
10062491
负责人：
Qing Chen
金额：
$ 41.61万
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/10062491
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 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 of activation protein Melanoma Cell Mesenchymal Metastatic Melanoma Metastatic malignant neoplasm to brain Modeling Neoplasm Metastasis Neuroglia Neurons Oleic Acids Organ PPAR Pathway PPAR gamma Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pharmacology Phenotype Play Primary Neoplasm Process Production Relapse Reporter Research Response Elements Role Sampling Seeds Signal Transduction Site Soil Stains Stromal Cells Systemic Therapy Techniques Testing Time Transitional Epithelium Unsaturated Fatty Acids Xenograft procedure aldehyde dehydrogenases astrogliosis base 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 pre-clinical promoter small molecule inhibitor spatiotemporal therapeutic target therapy resistant treatment strategy

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 PPAR 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 PPAR pathway in melanoma cells during brain metastasis. We will track the dynamic changes and effect of PPAR signaling in melanoma cells throughout the whole brain metastatic process. Moreover, PPAR 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 PPAR signaling in the invades melanoma cells. We hypothesize that astrocytes serve as ‘donor’ of unsaturated fatty acids, natural agonist of PPAR, 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.

项目摘要转移，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。罹患癌症。大脑是常见的转移部位之一。脑转移瘤，发生于晚期病程，已成为临床上的重大问题，因为它的发病率上升的结果是现有系统疗法的生存时间延长，疗效有限。转移是一个多步骤的过程，需要癌细胞和间质细胞之间复杂的相互作用，这个过程通常被称为 “种子和土壤假说”诞生于一个多世纪前。土壤，即微环境，不仅决定了转移的癌细胞的生长，但也有助于治疗抵抗。“种子”，侵袭的癌症细胞，直接修饰周围的大脑基质细胞。我们的长期目标是解剖这个建筑群癌细胞与脑基质细胞在转移过程中的相互作用。我们已经开发了新的体内和体外模型来解决我们对大脑理解的空白转移性生长的微环境控制。我们的数据表明，星形胶质细胞，最独特和最丰富的脑细胞，激活脑转移黑色素瘤细胞中的PPAR信号。通过集成式利用体外共培养试验和体内脑转移小鼠模型，Aim 1将描绘出 PPAR通路在黑色素瘤细胞脑转移中的作用我们将跟踪动态变化和影响在黑色素瘤细胞中，PPAR信号通路贯穿于整个脑转移过程。此外，PPAR 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将阐述星形胶质细胞如何在侵袭的黑色素瘤细胞中激活PPAR信号。我们假设星形胶质细胞是侵袭性黑色素瘤的不饱和脂肪酸的供体，PPAR的天然激动剂细胞。所获得的洞察力可能使我们能够机械地解构黑色素瘤脑转移并发展为临床资源较少的患者制定新的治疗策略。