Exosome-mediated Transfer of c-MET to Bone Marrow Progenitors Promotes Metastasis

外泌体介导的 c-MET 向骨髓祖细胞的转移促进转移

• 批准号: 8580357
• 负责人: DAVID CHARLES LYDEN
• 金额: $ 35.17万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580357
• 关键词: Adjuvant; Automobile Driving; Behavior; Biological Assay; Biological Markers; Blood; Blood Banks; Blood Circulation; Bone Marrow; Cells; Collaborations; Combined Modality Therapy; Data; Development; Diagnostic; Disease; Disease Progression; Distal; Early identification; Education; Evolution; Frequencies; Genetic; Genotype; Goals; Health; Hematopoietic; Immunophenotyping; In Vitro; Institution; Laboratories; Lead; MAP Kinase Gene; MET Oncogene; Malignant Neoplasms; Mediating; Melanoma Cell; Memorial Sloan-Kettering Cancer Center; Metastatic Melanoma; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Neoplasm Metastasis; Oncogene Proteins; Oncogenes; Pathway interactions; Patients; Phase; Phenotype; Play; Population; Pre-Clinical Model; Primary Neoplasm; Prognostic Marker; Proteomics; Publishing; Recurrent disease; Relapse; Research Personnel; Resources; Risk; Role; Sampling; Signal Transduction; Staging; Stem cells; Stromal Cells; Testing; Therapeutic; Tumor Suppressor Proteins; Tumor-Derived; Up-Regulation; cell type; chemokine; cytokine; follow-up; high risk; human FRAP1 protein; human disease; in vivo; in vivo Model; insight; melanoma; mouse model; novel; novel strategies; prevent; progenitor; programs; research study; response; therapeutic target; tool; transcriptomics; tumor; tumor growth; tumor microenvironment; tumor progression

DESCRIPTION (provided by applicant): Metastasis is the most devastating phase of tumor progression in all cancers as commonly observed in melanoma. Historically, researchers have focused on tumor phenotype and genotype in seeking strategies that block tumor metastasis. However, evidence accumulated in the past decade supports a crucial role for cells, as well as secreted factors such as cytokines, chemokines and exosomes in the surrounding tumor microenvironment as critical components regulating primary tumor growth and metastatic behavior. The goal of the proposed project is to determine the mechanisms through which tumor-derived microvesicles, known as exosomes and bone marrow-derived cells (BMDCs) promote the highly metastatic phenotype associated with melanoma. We will define the molecular mechanisms, molecules and pathways involved in mediating cross- talk between melanoma-derived exosomes, BMDCs and the metastatic niche microenvironment using complementary in vitro and in vivo models. Since biomarkers predictive of melanoma metastatic progression are lacking, we propose to determine whether exosome cargo and BMDCs can be used as novel indicators of metastatic burden in melanoma. We plan to develop therapeutic strategies to block the activation of pathways, specifically c-MET oncogene signaling, that confer a highly metastatic behavior in melanoma, and that, when up-regulated in hematopoietic progenitors by tumor-derived exosomes, lead to the development of pro- metastatic BMDC subsets. We propose that these strategies will prevent metastasis or hinder its progression by simultaneously reducing the mobilization and recruitment of BMDCs to primary tumor and metastatic niches. The development of novel approaches to analyze the contribution of tumor-derived exosomes to metastasis as well as their capacity to "educate" other cell types is further described in the current proposal. Importantly, we identify novel mechanisms and propose to dissect specific pathways, such as c-MET signaling, involved in BMDC "education" by melanoma exosomes. Our studies in melanoma patients are the first to investigate whether the levels of circulating bone marrow progenitor cells and tumor-secreted exosomes could identify patients with metastatic disease. Ultimately, we propose to explore the possibility that inhibition of specific exosome cargo molecules or their targets in hematopoietic progenitors could block the recruitment of BMDCs and other stroma cell types in melanoma, providing a valuable combination therapy for the management of human disease. Furthermore, we hypothesize that targeting tumor-derived exosome function will contribute to the reduction of metastases and relapses responsible for patient lethality in melanoma, providing a rationale for development of targeted therapeutic approaches. In summary, we will focus on studying the mechanisms through which exosomes regulate BMDC mobilization and recruitment to pre-metastatic and metastatic niches in melanoma models and melanoma patients.

描述(由申请人提供)：转移是所有癌症中最具破坏性的阶段，通常在黑色素瘤中观察到。从历史上看，研究人员在寻找阻断肿瘤转移的策略时，一直专注于肿瘤表型和基因型。然而，过去十年积累的证据支持细胞以及周围肿瘤微环境中的细胞因子、趋化因子和外切体等分泌因子作为调节原发肿瘤生长和转移行为的关键成分。这项拟议项目的目标是确定肿瘤来源的微泡，即外切体和骨髓来源细胞(BMDCs)促进与黑色素瘤相关的高转移表型的机制。我们将使用互补的体外和体内模型，确定在黑色素瘤来源的外切体、BMDCs和转移的生态位微环境之间调节串扰的分子机制、分子和途径。由于缺乏预测黑色素瘤转移进展的生物标志物，我们建议确定外切体Cargo和BMDCs是否可以作为黑色素瘤转移负荷的新指标。我们计划开发治疗策略来阻断通路的激活，特别是c-met癌基因信号，这些通路在黑色素瘤中具有高度转移的行为，并且当肿瘤来源的外体上调造血祖细胞时，导致促进转移的BMDC亚群的发展。我们认为，这些策略将通过同时减少BMDCs对原发肿瘤和转移壁龛的动员和募集来防止转移或阻碍其进展。目前的提案进一步描述了新方法的发展，以分析肿瘤来源的外切体对转移的贡献以及它们“教育”其他类型细胞的能力。重要的是，我们确定了新的机制，并建议剖析特定的途径，如c-met信号，参与黑色素瘤外切体对BMDC的“教育”。我们在黑色素瘤患者中的研究首次调查了循环骨髓祖细胞和肿瘤分泌外切体的水平是否可以识别转移性疾病患者。最终，我们建议探索抑制的可能性 在造血祖细胞中阻断特定的外体货运分子或其靶点可以阻断黑色素瘤中BMDCs和其他基质细胞类型的招募，为人类疾病的治疗提供了一种有价值的联合治疗方法。此外，我们假设，靶向肿瘤来源的外切体功能将有助于减少黑色素瘤患者致命性的转移和复发，为靶向治疗方法的发展提供了理论基础。综上所述，我们将重点研究在黑色素瘤模型和黑色素瘤患者中，外切体调节BMDC动员和募集到转移前和转移利基的机制。