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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，并且它们在区域淋巴结中的存在是临床上最重要的单一不良预后因素。一旦进入淋巴结，乳腺癌细胞就会进入循环系统并扩散到远处。在这种情况下，开发模型使我们能够定义肿瘤细胞最初侵入淋巴管的机制，并开发针对这些机制的筛选药物的平台对于我们来说至关重要。我们的工作假设是，概括乳腺癌细胞和淋巴微血管内皮细胞之间相互作用的 3D 模型可用于识别与侵入淋巴管和淋巴管生成相关的药物途径。我们的理由是，体外确定的途径将至少重现患者样本中存在的途径的一个子集，从而使我们能够为新的治疗策略定义可药物节点。转化我们的研究的关键是筛选平台，该平台可用于在 3D 环境下可重复地生长乳腺细胞和淋巴细胞，并实时测试和量化活细胞对治疗干预的动态反应。我们的具体目标是： 1）建立重现乳腺癌细胞和淋巴微血管内皮细胞之间相互作用的最佳条件； 2）设计、制造和测试可用于成像、治疗靶点识别和药物筛选的新型微流控平台； 3) 对于原理验证研究，确定候选治疗靶点并在患者样本中进行验证； 4) 对针对候选治疗靶点的药物进行初步筛选。我们将使用创新的 4D（3D + 时间）培养来模拟人乳腺癌细胞和人淋巴微血管内皮细胞之间的相互作用。我们将构建新型微流体平台，用于新型 3D 培养物的长期生长，通过共焦显微镜对培养物进行成像，分析因这些培养物中的动态相互作用而改变的生化和免疫化学途径，识别潜在的治疗靶点并筛选针对这些靶点和相关途径的药物。有效的筛选要求我们的模型具有高度可重复性，并且我们使用的平台允许我们在多个浓度下测试许多不同的药物。我们在构建可用于细胞培养的微型平台（包括作为患者的假肢装置）方面拥有丰富的经验。我们的研究应该加速识别可能针对个体患者的有效药物。