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

• 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
• 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

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 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·霍普金斯大学提供广泛的资源和职业发展计划。 Fane博士已经集合 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，治疗无法提供持久的反应。尽管 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 远端器官中的休眠状态在治疗期间持续存在，但临床上无法检测到。最终，这些细胞将 从休眠状态“重新激活”，形成转移性集落，现在对治疗产生抗药性。很少有实验室专注于 关于黑色素瘤休眠，因此，目前没有治疗或诊断工具来识别和靶向 休眠细胞。拟议的研究基于 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 肺。目前尚不清楚“重新激活”的细胞如何克服免疫系统的靶向、生长限制线索 来自肺成纤维细胞，或者它们如何对治疗产生抗药性。 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以改变细胞外基质的分泌，将其从 休眠促进黑色素瘤生长。费恩博士还表明，“重新激活”后 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。 对免疫治疗有抵抗力的患者的特征。最后，费恩博士证明，“重新激活”的黑色素瘤细胞 分泌高水平的可溶性蛋白 PROS1，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 休眠。 Fane 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 至α-PD1。完成本提案中的科学目标将使范斯博士的科学性和专业性得到发展 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。