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:8547040
- 负责人:
- 金额:$ 54.48万
- 依托单位:
- 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:
- 关键词:3-DimensionalAddressAnimal ModelArchitectureBehaviorBiologicalBiological MarkersBiomedical EngineeringBlood CirculationBone MarrowBone Marrow CellsBreastBreast Cancer CellBypassCancer ControlCancer PatientCell membraneCell physiologyCellsClinicalCoculture TechniquesComplexDataDiagnosisDiagnosticDiseaseDissectionDistantEmployee StrikesEpithelial CellsEquilibriumExhibitsExtracellular MatrixFibroblastsFibronectinsGoalsGrowth FactorHome environmentHormonesImmuneIntegrinsLaboratoriesLungMalignant - descriptorMalignant NeoplasmsMammary NeoplasmsMeasuresMediatingMelanoma CellMembraneMetastatic MelanomaModelingNeoplasm MetastasisNormal CellPatientsPhasePlasmaPlayPrimary NeoplasmProteinsProteomicsRNARegulationRelapseRoleSeedsSignal TransductionSignaling MoleculeSiteSolid NeoplasmSpecific qualifier valueSpecimenStagingStromal CellsTestingTherapeuticTissue MicroarrayTissuesTransactTumor SubtypeTumor-DerivedVariantVesicleWorkadvanced diseaseangiogenesisbasebonecell growthchemokineclinically significantconditioningcytokineinterestmalignant breast neoplasmmalignant phenotypemelanomamolecular recognitionneoplastic celloutcome forecasttherapeutic targetthree-dimensional modelingtriple-negative invasive breast carcinomatumortumor growthtumor microenvironmenttumor progressionuptake
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):我们的合作项目扩展了“转移利基”作为乳腺恶性肿瘤重要决定因素的概念。在过去的十年中,我们已经增强了对微环境作为肿瘤生长和转移的潜在驱动因素的概念理解。我们的下一个挑战是解剖驱动乳腺易感上皮细胞恶性行为的精确细胞相互作用,以及它们的第二家园(即它们传播到的地方,以及它们以“休眠”方式等待再次攻击的地方)。基于Lyden博士对转移前生态位的开创性识别和分子解剖,以及Bissell博士对细胞外基质(ECM)相互作用的开创性分析,明确了正常与恶性行为以及乳腺肿瘤微环境调节的关键作用,我们设想了原发性和继发性肿瘤部位的生态位。这些是由乳腺肿瘤细胞及其基质之间的串扰控制的,由分泌因子如趋化因子/细胞因子,ECM成分和外泌体介导,其中包含这两类分子。具体来说,我们假设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,我们建议从BC患者和健康对照中分离外泌体(研究较少的由膜包围的小泡,充满由肿瘤细胞释放的可能导致潜在危害的蛋白质和RNA),以确定外泌体含量是否预测患者的分期、转移负担和生存。我们将定义乳腺肿瘤源性外泌体的蛋白质组学特征,这些特征可用于临床诊断并可能提供治疗靶点。我们还将利用三维共培养模型来确定恶性进展和伴随的组织结构破坏如何影响外泌体的释放和潜在恶意内容的结合。这些外泌体的功能将通过测量它们激活邻近“正常”乳腺基质细胞的能力和从这些细胞中引发相互的肿瘤促进功能来测试。最后,我们将利用动物模型和3D共培养来测量BC外泌体与骨髓细胞的相互作用,以及外泌体是否引发骨髓内转移前生态位的形成或破坏组织内休眠生态位。所有拟议的研究都将通过靶向外泌体内的蛋白质含量来确定这样做是否会消除肿瘤促进作用,从而保持治疗重点。我们工作的长期目标是鉴定外泌体中包含的可靶向分子,以阻止肿瘤进展和阻止转移性复发。
项目成果
期刊论文数量(0)
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MINA BISSELL其他文献
MINA BISSELL的其他文献
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{{ truncateString('MINA BISSELL', 18)}}的其他基金
Definition of the Microenvironment in Breast Cancer
乳腺癌微环境的定义
- 批准号:
9107039 - 财政年份:2016
- 资助金额:
$ 54.48万 - 项目类别:
Definition of the Microenvironment in Breast Cancer
乳腺癌微环境的定义
- 批准号:
9906598 - 财政年份:2016
- 资助金额:
$ 54.48万 - 项目类别:
Definition of the Microenvironment in Breast Cancer
乳腺癌微环境的定义
- 批准号:
9906592 - 财政年份:2016
- 资助金额:
$ 54.48万 - 项目类别:
Definition of the Microenvironment in Breast Cancer
乳腺癌微环境的定义
- 批准号:
9754593 - 财政年份:2016
- 资助金额:
$ 54.48万 - 项目类别:
Definition of the Microenvironment in Breast Cancer
乳腺癌微环境的定义
- 批准号:
9320815 - 财政年份:2016
- 资助金额:
$ 54.48万 - 项目类别:
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
- 批准号:
8366181 - 财政年份:2012
- 资助金额:
$ 54.48万 - 项目类别:
Myoepithelial cell differentiation defects in ductal carcinoma in situ (DCIS)
导管原位癌 (DCIS) 中的肌上皮细胞分化缺陷
- 批准号:
8322312 - 财政年份:2009
- 资助金额:
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Role of metalloproteinases in mammary gland remodeling
金属蛋白酶在乳腺重塑中的作用
- 批准号:
7911061 - 财政年份:2009
- 资助金额:
$ 54.48万 - 项目类别:
Myoepithelial cell differentiation defects in ductal carcinoma in situ (DCIS)
导管原位癌 (DCIS) 中的肌上皮细胞分化缺陷
- 批准号:
8528505 - 财政年份:2009
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EXTRACELLULAR MATRIX ON B-CASEIN GENE EXPRESS IN NORMAL MAMMARY EPITHELIAL CELL
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7957446 - 财政年份:2008
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