Understanding PPARgamma signaling in melanoma brain metastasis

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PPARγ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 PPARγ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，PPARγ信号通路贯穿于整个脑转移过程。此外，PPARγ 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PPARγ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，PPARγ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。

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.