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: 10813230
• 负责人: Mitchell Edward Fane
• 金额: $ 24.9万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 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 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10813230
• 关键词: Address; Aging; Antibodies; BRAF gene; Behavior; Bioinformatics; CD8-Positive T-Lymphocytes; Cell Communication; Cell secretion; 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; Immunosuppression; Immunotherapy; Knowledge; Left; Ligands; Liquid Chromatography; Lung; MEKs; Malignant Neoplasms; Manuscripts; Melanoma Cell; Metastatic Melanoma; Micrometastasis; Migration Assay; Modeling; Molecular; Mus; Myeloid-derived suppressor cells; Nature; Neoplasm Metastasis; Organ; Pathology; Pathway interactions; Patients; Phenotype; Population; Primary Neoplasm; Process; Production; Program Development; Proliferating; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Recombinants; Regulatory T-Lymphocyte; Research Personnel; Residual Neoplasm; Resistance; Resource Development; Role; Signal Transduction; Site; Sorting; Source; Stromal Cells; Structure of parenchyma of lung; T-Lymphocyte; TNFRSF10B gene; Techniques; Thick; Tissues; Training; Tumor Tissue; Up-Regulation; Visceral; age related; aged; cancer cell; career development; clinical translation; comparative; crosslink; diagnostic tool; immune clearance; in vivo; insight; melanoma; mortality; mouse model; neoplastic cell; novel; patient subsets; permissiveness; 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.

项目摘要 这条独立职业发展之路提案的目标是请求支持费恩博士 开展肿瘤休眠和潜在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， 转移性生长和对治疗的抗性。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。费恩博士召集了 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 一部分患者最初对治疗表现出显着的反应，他们中的大多数将有肿瘤细胞躺在 在治疗期间持续存在但临床上无法检测到的远端器官中休眠。最终，这些细胞将 从休眠中“重新激活"形成转移性菌落，现在对治疗有抵抗力。很少有实验室 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是基于Fanes博士的新发现， 激酶受体MER促进癌症生长，这使得黑色素瘤细胞内休眠的黑色素瘤细胞“重新激活”。 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，生长限制性线索 或者它们是如何对治疗产生抗药性的。费恩斯博士的初步数据首先显示， MER高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， 休眠促进黑色素瘤生长。费恩博士还表明，在“重新激活”之后， 在肺内黑色素瘤中，髓源性抑制细胞（MDSC）和T调节细胞（T-regulatory cell，T-regulatory cell，T-regulatory cell）增加。 癌细胞通常是一种常见的癌细胞，它抑制免疫系统靶向癌细胞进行破坏， 对免疫疗法有抵抗力的患者的特征。最后，费恩博士已经证明，“重新激活”的黑素瘤细胞 分泌高水平的可溶性蛋白质PROS 1，已知其参与调节 在其他疾病状态下的MDSC、TCFs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 PROS 1调节肺成纤维细胞以促进生长和治疗抗性; 2）研究机制 MER诱导的肺中黑色素瘤细胞分泌PROS 1调节免疫细胞和应答 α-PD1。本提案中科学目标的完成将使Fanes博士的科学和专业水平得到提高。 技能，需要成为一个独立的调查员进入休眠领域，重要的是，将提供 对癌细胞如何克服休眠，转移性疾病的靶向和免疫疗法的新见解。