4D Microfluidic Platforms for Targeting Breast Cancer:Lymphatic Interactions

用于靶向乳腺癌的 4D 微流体平台：淋巴相互作用

基本信息

批准号：
8493506
负责人：
BONNIE F SLOANE
金额：
$ 19.84万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8493506
关键词：
4D Imaging Adherent Culture Animal Model Architecture Biochemical Biochemical Process Biological Assay Biosensor Blood Circulation Breast Breast Cancer Cell Breast Cancer Detection Breast Carcinoma Cancer Biology Cancer cell line Cell Communication Cell Culture Techniques Cell Line Cells Coculture Techniques Computer software Confocal Microscopy Development Distant Distant Metastasis Drug Targeting Endothelial Cells Engineering Epithelial Cells Fibroblasts Future Goals Growth Human Image Image Analysis In Vitro Individual Life Lymph Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic Metastasis Lymphatic vessel Malignant Epithelial Cell Mammary gland Measurement Mediating Microfluidics Modeling Monitor Names Neoplasm Metastasis Pathway interactions Patients Pharmaceutical Preparations Preclinical Drug Evaluation Premalignant Process Prognostic Factor Prosthesis Proteolysis Research Research Personnel Route Sampling Site Specimen Temperature Testing Therapeutic Intervention Three-Dimensional Image Three-dimensional analysis Time Tissue Engineering Translations Treatment Efficacy Tumor Cell Invasion Work abstracting cell type cellular imaging chemokine design experience flexibility high throughput screening in vivo innovation lymph nodes macrophage malignant breast neoplasm malignant phenotype miniaturize novel novel therapeutics optical imaging public health relevance response screening therapeutic target three-dimensional modeling triple-negative invasive breast carcinoma tumor

项目摘要

DESCRIPTION (provided by applicant): Abstract Lymphatic metastasis is the predominant route of the initial spread of breast cancer cells and their presence in regional lymph nodes is the single most clinically important negative prognostic factor. Once in lymph nodes, breast cancer cells can find their way into the circulation and spread to distant sites. This being the case it is critically important for us to develop models that will allow us to define mechanisms fo the initial invasion of tumor cells into lymph vessels and to develop platforms for screening drugs that target those mechanisms. Our working hypothesis is that 3D models that recapitulate the interactions between breast carcinoma cells and lymphatic microvascular endothelial cells can be used to identify druggable pathways associated with invasion into lymphatic vessels and lymphangiogenesis. Our rationale is that the pathways identified in vitro will recapitulate at leas a subset of those present in patient samples and thereby allow us to define druggable nodes for novel therapeutic strategies. Critical to translation of our studies will be screening platforms tht can be used to reproducibly grow breast and lymphatic cells in 3D and test and quantify dynamic responses of live cells to therapeutic interventions in real-time. Our Specific Aims are to: 1) Establish optimal conditions for recapitulating in vivo interactions between breast carcinoma cells and lymphatic microvascular endothelial cells; 2) Design, fabricate and test novel microfluidic platforms that can be used for imaging, identification of therapeutic targets and drug screening; 3) For proof-of-principle studies, Identify a candidate therapeutic target and validate in patient samples; and 4) Perform initial screening of agents that target the candidate therapeutic target. We will use innovative 4D (3D + time) cultures to model the interactions between human breast carcinoma cells and human lymphatic microvascular endothelial cells. We will construct novel microfluidic platforms for long-term growth of the novel 3D cultures, image the cultures by confocal microscopy, analyze biochemical and immunochemical pathways that are altered by the dynamic interactions in these cultures, identify potential therapeutic targets and screen drugs directed against those targets and associated pathways. Effective screening requires that our models be highly reproducible and that we use platforms that allow us to test many different drugs at multiple concentrations. We have extensive experience in constructing miniaturized platforms that can be used for cell culture, including as prosthetic devices in patients. Our studies should accelerate the identification of effective drugs potentially ones targeted to individual patients.

描述（由申请人提供）：摘要淋巴转移是乳腺癌细胞初始扩散的主要途径，它们在区域淋巴结中的存在是最重要的临床上最重要的负预后因素。一旦进入淋巴结，乳腺癌细胞就可以进入循环系统并扩散到远处。在这种情况下，对于我们而言，开发模型至关重要，这将使我们能够将肿瘤细胞最初侵袭到淋巴管中的初始侵袭，并开发用于筛选针对这些机制的药物的平台。我们的工作假设是，概括乳腺癌细胞与淋巴微血管内皮细胞之间相互作用的3D模型可用于鉴定与侵袭淋巴管和淋巴管生成有关的可药途径。我们的理由是，在体外鉴定的途径将在LEA中概括患者样品中存在的部分，从而使我们能够为新的治疗策略定义可药的节点。对我们的研究的翻译至关重要的是筛查平台可用于在3D中可重复地生长乳房和淋巴细胞，并测试和量化活细胞实时对治疗干预措施的动态反应。我们的具体目的是：1）建立最佳条件，以概括乳腺癌细胞与淋巴微血管内皮细胞之间的体内相互作用； 2）设计，制造和测试可用于成像，鉴定治疗靶标和药物筛查的新型微流体平台； 3）对于原则研究证明，请确定候选治疗靶标并在患者样本中验证； 4）对靶向候选治疗靶标的药物进行初次筛选。我们将使用创新的4D（3D +时间）培养物来建模人类乳腺癌细胞与人淋巴微血管内皮细胞之间的相互作用。我们将构建新型的微流体平台，用于新型3D培养物的长期生长，通过共聚焦显微镜对培养物进行形象，分析生化和免疫化学途径，这些途径因这些培养物中的动态相互作用而改变，并确定潜在的治疗靶标和针对这些靶标和相关途径的药物。有效的筛选要求我们的模型高度可重现，并且我们使用的平台使我们能够以多种浓度测试许多不同的药物。我们在构建可用于细胞培养的小型平台方面拥有丰富的经验，包括作为患者的假体设备。我们的研究应加速鉴定针对个别患者的有效药物。