Characterization and Functional Analysis of Breast Cancer Secreted Exosomes in Ma

乳腺癌分泌的外泌体的表征和功能分析

基本信息

批准号：
8366181
负责人：
MINA BISSELL
金额：
$ 62.55万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8366181
关键词：
3-Dimensional Address Animal Model Architecture Behavior Biological Biological Markers Biomedical Engineering Blood Circulation Bone Marrow Bone Marrow Cells Breast Breast Cancer Cell Bypass Cancer Control Cancer Patient Cell membrane Cell physiology Cells Clinical Coculture Techniques Complex Data Diagnosis Diagnostic Disease Dissection Distant Employee Strikes Epithelial Cells Equilibrium Exhibits Extracellular Matrix Fibroblasts Fibronectins Goals Growth Factor Home environment Hormones Immune Integrins Laboratories Lung Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Measures Mediating Melanoma Cell Membrane Metastatic Melanoma Modeling Neoplasm Metastasis Normal Cell Patients Phase Plasma Play Primary Neoplasm Proteins Proteomics RNA Regulation Relapse Role Seeds Signal Transduction Signaling Molecule Site Solid Neoplasm Specific qualifier value Specimen Staging Stromal Cells Testing Therapeutic Tissue Microarray Tissues Transact Tumor Subtype Tumor-Derived Variant Vesicle Work advanced disease angiogenesis base bone cell growth chemokine clinically significant conditioning cytokine interest malignant breast neoplasm malignant phenotype melanoma molecular recognition neoplastic cell outcome forecast therapeutic target three-dimensional modeling triple-negative invasive breast carcinoma tumor tumor growth tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Our collaborative project expands on the concept of 'metastatic niche' as an important determinant of malignancy in the breast. Over the past decade, we have enhanced our conceptual understanding of the microenvironment as a potential driver of tumor growth and metastasis. Our next challenge is to dissect the precise cellular interactions that drive malignant behaviors of susceptible epithelial cells in the breast s well as their secondary homes (i.e., those that they disseminate to, and where they sit in a 'dormant' fashion waiting to strike again). Based on Dr. Lyden's groundbreaking recognition and molecular dissection of the pre-metastatic niche and Dr. Bissell's pioneering analysis of cell-extracellular matrix (ECM) interactions specifying normal versus malignant behavior and the crucial role of the microenvironmental regulation of breast tumors, we conceive of niches within primary and secondary tumor sites. These are governed by the crosstalk between breast tumor cells and their stroma that is mediated by secreted factors like chemokines/cytokines, ECM components, and exosomes, which contain both classes of molecules. Specifically, we hypothesize that exosome-mediated crosstalk in the primary tumor microenvironment and within the bone marrow microenvironment facilitates tumor progression. Since biomarkers predictive of breast cancer (BC) progression and metastasis are lacking, we propose to isolate exosomes (poorly studied small vesicles surrounded by membranes and full of proteins and RNA that are released by tumor cells that could cause potential harm) from BC patients and healthy controls to determine whether exosome content are predictive of patient stage, metastatic burden and survival. We will define proteomic signatures of breast tumor-derived exosomes that can be used clinically for diagnosis and may provide therapeutic targets. We will also utilize 3-dimensional co-culture models to determine how malignant progression and concomitant disruption of tissue architecture influences the exosome release and incorporation of potentially malicious content. The function of these exosomes will be tested by measuring their ability to activate neighboring 'normal' breast stromal cells and to elicit reciprocal tumor-promoting functions from these cells. Finally, we will utilize animal models and 3D co-cultures to measure BC exosome interaction with bone marrow cells and whether exosomes elicit formation of pre-metastatic niches within the bone marrow or disrupt dormant niches within the tissue. All the proposed studies will keep a therapeutic focus by targeting protein content within exosomes to determine whether doing so eliminates tumor-promoting effects. The long-term objectives of our work are to identify targetable molecules contained within exosomes to hinder tumor progression and halt metastatic relapse.

描述（由申请人提供）：我们的协作项目扩展了“转移性生态位”的概念，这是乳房中恶性肿瘤的重要决定因素。在过去的十年中，我们增强了对微环境的概念理解，作为肿瘤生长和转移的潜在驱动力。我们的下一个挑战是剖析乳房及其次要房屋中易感上皮细胞的恶性行为的精确细胞相互作用（即，它们分散到乳房的房屋，以及以“休眠”的方式等待再次罢工）。基于莱顿博士的开创性识别和分子解剖，对中迁移裂料的开创性识别和贝塞尔博士对细胞 - 骨细胞基质（ECM）相互作用的开创性分析，指定了正常行为，以及我们在乳房肿瘤的微观环境调节中的重要作用，我们认为，我们会在乳房肿瘤中的微观调节。这些由乳腺肿瘤细胞及其基质之间的串扰控制，这些串扰由分泌因子（例如趋化因子/细胞因子，ECM成分和外部体）介导，这些因素含有两种分子。具体而言，我们假设在原发性肿瘤微环境和骨髓微环境中，外泌体介导的串扰促进了肿瘤的进展。由于缺乏预测乳腺癌（BC）进展和转移的生物标志物，因此我们建议分离外泌体（被膜包围的小囊泡较少，肿瘤细胞包围的小囊泡可能由肿瘤细胞释放，这些肿瘤细胞可能会造成潜在危害的肿瘤细胞）对BC患者的潜在伤害），以确定exosome含量是否可以预测患者阶段，并保留了敏感的伯爵，并保持了敏感的伯爵疗法。我们将定义乳腺肿瘤衍生的外泌体的蛋白质组学特征，这些特征可在临床上用于诊断并可能提供治疗靶标。我们还将利用三维共培养模型来确定组织结构的恶性进展和伴随破坏如何影响外部释放和纳入潜在的恶意含量。这些外泌体的功能将通过测量其激活相邻的“正常”乳腺基础细胞并从这些细胞中引起相互促进肿瘤功能的能力来测试。最后，我们将利用动物模型和3D共培养物来测量BC外泌体与骨髓细胞的相互作用，以及外泌体是否会在骨髓内形成骨髓前的壁ni，或破坏组织内的休眠壁ni。所有提出的研究将通过靶向外泌体内的蛋白质含量来确定这样做是否消除肿瘤促进作用，以保持治疗焦点。我们工作的长期目标是确定外泌体内包含的可靶向分子，以阻止肿瘤进展和停止转移性复发。