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

MER/PROS1 在促进基质诱导的转移性黑色素瘤休眠中的作用

基本信息

批准号：
10526077
负责人：
Mitchell Edward Fane
金额：
$ 12.13万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10526077
关键词：
Address Aging Antibodies BRAF gene Behavior Bioinformatics CD8-Positive T-Lymphocytes Cells Cessation of life Clinical Communication Cues Data Disease Distal Doxycycline Event Excision Extracellular Matrix Family member Fiber Fibroblasts Flow Cytometry Genetic Induction Global Change Goals Growth IL2RA gene Image Immune Immune Targeting Immune system Immunology Immunotherapy Knowledge Lead Left Ligands Liquid Chromatography Lung MEKs Malignant Neoplasms Manuscripts Melanoma Cell Metastatic Melanoma Micrometastasis Migration Assay Modeling Molecular Mus Myeloid-derived suppressor cells Neoplasm Metastasis Organ Pathway interactions Patients Phenotype Population Primary Neoplasm Process Production Program Development Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Recombinants Regulatory T-Lymphocyte Research Personnel Residual Tumors Resistance Resource Development Role Signal Transduction Site Source Stromal Cells Structure of parenchyma of lung T-Lymphocyte TNFRSF10B gene Techniques Thick Tissues Training Tumor Tissue Up-Regulation Visceral age related aged base cancer cell career development comparative crosslink diagnostic tool immune clearance in vivo insight melanoma mortality mouse model neoplastic cell novel patient subsets programmed cell death protein 1 protein expression receptor response senescence single-cell RNA sequencing skills tandem mass spectrometry therapy resistant translational therapeutics tumor tumor growth tumor immunology tumor-immune system interactions

项目摘要

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.

项目概要此独立职业发展之路提案的目标是请求对费恩博士的支持开展肿瘤休眠和基础癌症免疫学和生物信息学技术方面的培训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本提案中概述的培训计划将利用转移性生长和治疗耐药性。费恩博士汇集了约翰·霍普金斯大学提供的广泛资源和职业发展计划。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，而治疗无法提供持久的反应。一部分患者最初对治疗表现出显着的反应，其中大多数患者体内都存在肿瘤细胞这些细胞在治疗期间持续存在于远端器官中，但临床上无法检测到。从休眠状态“重新激活”形成转移性集落，现在对治疗产生抗药性很少有实验室关注这一点。关于黑色素瘤休眠，因此，目前没有治疗方法或诊断工具来识别和靶向拟议的研究是基于 Fanes 博士的新发现，即酪氨酸上调激酶受体 MER 促进癌症生长，从而“重新激活”体内休眠的黑色素瘤细胞目前尚不清楚“重新激活”的细胞如何克服免疫系统的靶向、生长限制信号。 Fanes 博士的初步数据首先表明，肺成纤维细胞如何对治疗产生抗药性。 MERhigh 黑色素瘤细胞调节肺成纤维细胞以改变细胞外基质的分泌，将其从费恩博士还表明，在“重新激活”后，促进黑色素瘤生长。肺内黑色素瘤的发生，骨髓源性抑制细胞 (MDSC) 和 T 调节细胞增加（Treg）细胞抑制免疫系统针对癌细胞进行破坏，通常是一种常见的细胞。最后，费恩博士发现，黑色素瘤细胞“重新激活”。分泌高水平的可溶性蛋白 PROS1，已知该蛋白参与调节其他疾病状态下的 MDSC、Treg 和肺成纤维细胞，但尚未在转移性肿瘤中进行研究 Fane博士宿舍将探索以下科学目标： 1）确定MER是否诱导分泌 PROS1 调节肺成纤维细胞以促进生长和治疗抵抗，2) 研究其机制 MER 诱导肺部黑色素瘤细胞分泌 PROS1，从而调节免疫细胞和反应完成本提案中的科学目标将使 Fanes 博士更加科学和专业。成为休眠领域的独立调查员所需的技能，重要的是，将提供关于癌细胞如何克服休眠、转移性疾病中的靶向和免疫疗法的新见解。