The role of MER/PROS1 in promoting stromal induced emergence from metastatic melanoma dormancy

项目摘要 《独立之路》职业发展提案的目标是请求对费恩博士的支持 开展有关肿瘤休眠、潜在癌症免疫学和生物信息学技术的培训，以 研究位于转移组织内的休眠黑色素瘤细胞如何调节基质细胞以促进 转移性生长和对治疗的抵抗。本提案中概述的培训计划将利用 约翰霍普金斯大学提供的广泛资源和职业发展计划。费恩博士已经组装好了 一个由黑色素瘤、休眠、免疫学和生物信息学领域的领导者组成的团队将指导他的培训。 转移是黑色素瘤死亡的最大原因，治疗未能提供持久的反应。而当 一部分患者最初对治疗表现出显著的反应，他们中的大多数都会有肿瘤细胞 在远端器官中休眠，在治疗期间持续存在，但在临床上无法检测到。最终，这些细胞将 从休眠状态“重新激活”形成转移性集落，现在抵抗治疗。很少有实验室专注于 关于黑色素瘤的休眠，因此，目前还没有治疗方法或诊断工具来识别和靶向 休眠细胞。拟议的研究是基于Fanes博士的新发现，即上调酪氨酸 激酶受体聚合体促进癌症生长，使处于休眠状态的黑色素瘤细胞在 阿龙。目前尚不清楚重新激活的细胞如何克服免疫系统的靶向，生长受限的信号 肺成纤维细胞，或它们如何对治疗产生抵抗力。Fanes博士的初步数据首先表明 MERHigh黑色素瘤细胞调节肺成纤维细胞改变细胞外基质的分泌，使其从 休眠促进了黑色素瘤的生长。费恩博士还表明，在重新激活之后 在肺内的黑色素瘤中，髓系来源的抑制细胞(MDSCs)和T调节细胞增加 (Tregs)抑制免疫系统以破坏癌细胞为目标的细胞，通常是 免疫治疗耐药患者的特征。最后，费恩博士已经证明，重新激活的黑色素瘤细胞 分泌高水平的可溶性蛋白PROS1，这是已知参与调节的活性 MDSCs、Tregs和肺成纤维细胞在其他疾病状态下，但尚未被研究为转移性 休眠。费恩博士将探索以下科学目标：1)确定MER是否诱导分泌 PROS1调节肺成纤维细胞促进生长和治疗耐药2)探讨其机制 Mer诱导肺内黑色素瘤细胞分泌PROS1调节免疫细胞和反应 至α-pd1。该提案中的科学目标的完成将使Fanes博士的科学和专业发展 成为休眠领域的独立调查员所需的技能，而且重要的是，将提供 对癌细胞如何在潜伏性、转移性疾病中克服靶向和免疫疗法的新见解。

Project Summary The goals of this Pathway to Independence Career Development proposal are to request support for Dr. Fane to develop training in tumor dormancy and underlying cancer immunology and bioinformatics techniques to investigate how dormant melanoma cells located within metastatic tissues can regulate stromal cells to facilitate metastatic outgrowth and resistance to therapy. The training plan outlined in this proposal will take advantage of the extensive resources and career development programs available at Johns Hopkins. Dr. Fane has assembled a team of leaders in the field of melanoma, dormancy, immunology, and bioinformatics who will guide his training. Metastasis is the largest cause of melanoma deaths, with treatments failing to provide a durable response. While a subset of patients show-remarkable responses initially to therapy, most of them will have tumor cells lying dormant in distal organs that persist during therapy but are clinically undetectable. Eventually, these cells will ‘reactivate’ from dormancy to form metastatic colonies, now resistant to therapy. There are few labs that focus on melanoma dormancy and as such, there are no current treatments or diagnostic tools to identify and target dormant cells. The proposed studies are based on Dr. Fanes novel findings that upregulation of the tyrosine kinase receptor MER promotes cancer growth, which allows ‘reactivation’ of dormant melanoma cells within the lung. It isn’t known how ‘reactivated’ cells overcome targeting by the immune system, growth restrictive cues from lung fibroblasts, or how they become resistant to therapy. Dr. Fanes preliminary data first shows that MERhigh melanoma cells regulate lung fibroblasts to alter secretion of the extracellular matrix, changing it from being dormancy promoting to allowing melanoma outgrowth. Dr Fane has also shown that following ‘reactivation’ of melanoma within the lung, there is an increase in Myeloid Derived Suppressor Cells (MDSCs) and T-regulatory (Tregs) cells which inhibit the immune system from targeting cancer cells for destruction and are often a common feature in patients resistant to immunotherapy. Finally, Dr. Fane has shown that ‘reactivated’ melanoma cells secrete high levels of the soluble protein PROS1, which is known to be involved in regulating the activity of MDSCs, Tregs, and lung fibroblasts within other disease states, but has not been investigated in metastatic dormancy. Dr. Fane will explore the following scientific aims: 1) Determine whether MER induced secretion of PROS1 regulates lung fibroblast to promote outgrowth and therapy resistance and 2) Investigate the mechanism by which MER induced secretion of PROS1 by melanoma cells in the lung regulates immune cells and response to α-PD1. The completion of the scientific aims in this proposal will develop Dr. Fanes scientific and professional skills that are required to be an independent investigator into the field of dormancy and importantly, will provide novel insight into how cancer cells overcome targeted and immunotherapies in dormant, metastatic disease.