An Engineered Tissue Model of Aged Mammary Microenvironment

项目摘要 据报道，乳腺组织微环境的老化形成了促进肿瘤进展的肥沃土壤。AS 组织止血在衰老过程中演变，发展出能够探索肿瘤的模型 衰老生态位的进展对于了解疾病、识别关键途径和发现 可以接受治疗干预的控制点。老年乳房组织的系统查询 由于1)缺乏老化的正常乳房组织(理想状态)，环境一直具有挑战性，成本也高得令人望而却步 控制)用于组织微环境分析以及2)使用时长时间老化过程的逻辑屏障 实验小鼠模型。一种完全特征化的组织工程化乳房模型，忠实地概括了 乳腺癌在模拟衰老组织中的发展将成为研究乳腺癌的新平台 进展，并将为乳腺癌研究带来新的视角。使用微型制造的组织 工程模型，我们可以探索是什么构成了允许的老化基质环境 例如基质硬度、基质成分、基质细胞密度和组织等变量。 这项拟议工作的目标是建立一种模拟衰老的乳房组织工程(ABTe)，将用于 为了表征导致老化组织中允许环境的因素，包括物理因素， 化学和细胞信号，并调查治疗调节是否可以影响肿瘤的进展 老龄化的微环境。具体地说，我们的目标是1)表征生物物理特性和生化特性 老年乳腺组织细胞外基质的组成；2)ABTe系统的建立和细胞外基质模型的建立 通过调整与衰老相关的ECM因素，包括ECM硬度、ECM成分和基质，实现异质性 脂肪细胞的空间分布，然后3)通过运行测试所开发的ABTe的临床相关性和有效性 预防导管原位癌向浸润性导管转化的化学预防试验 癌症(IDC)。为了实现这些目标，我们将结合我们在组织工程和乳腺癌方面的专业知识。 研究。一旦完全实施和功能验证，我们预计我们最先进的组织工程学 ABTe癌症模型将成为基础癌症和转化性癌症的下一代研究平台 研究和高通量药物发现。组织工程化ABTe将极大地促进研究工作 在重要的，虽然传统上较难接触到的癌症研究和其他领域。

Project Summary Aging of breast tissue microenvironment has reported to form a fertile soil facilitating tumor progression. As tissue hemostasis evolves over the course of aging, developing models that enable the exploration of tumor progression in aging niche is important for understanding the disease, identifying crucial pathways, and finding control points that could be amenable to therapeutic intervention. Systematic inquiry of the aged breast tissue environment has been challenging and cost prohibitive, due to 1) lack of aged NORMAL breast tissue (an ideal control) for tissue microenvironment analysis and 2) the logistic barrier of lengthy aging process when using experimental mouse models. A fully characterized, tissue engineered breast model that faithfully recapitulates breast cancer development in an aging-mimicking tissue would be a novel platform for studying breast cancer progression, and would bring a new perspective to breast cancer research. Using a microfabricated tissue engineered model, we can explore what constitutes a permissive aging stromal environment by modulating variables such as matrix stiffness, matrix components, stromal cell density and organization, etc. The central goals of the proposed effort are to establish an Aging-mimicking Breast Tissue engineered (ABTe) that will be used to characterize the factors that contribute to the permissive environment in aging tissues, including the physical, chemical, and cellular cues, and to investigate whether therapeutic modulation can affect tumor progression in aging microenvironment. Specifically we aim to 1) Characterize biophysical properties and biochemical composition of extracellular matrices (ECM) of aged breast tissue; and 2) Build ABTe system and model ECM heterogeneity by tuning aging-related ECM factors including ECM stiffness, ECM composition, and stromal adipocytes spatial distribution, and then 3) test the clinical relevance and power of the developed ABTe by running chemoprevention trails for prevention of transition from Ductal Carcinoma In Situ (DCIS) to Invasive Ductal Carcinoma (IDC). To achieve these goals, we will combine our expertise of tissue engineering and breast cancer research. Once fully implemented and functionally validated, we expect our state-of-the-art tissue engineered ABTe cancer model to serve as the next-generation research platform for both basic and translational cancer research and high-throughput drug discovery. The tissue engineered ABTe will greatly facilitate research efforts in important, while traditionally less accessible, areas of cancer research and beyond.