Bioengineering 3-D Models for Breast Cancer Therapy

这项提议的中心目标是建立肺癌和乳腺癌这两种上皮性癌症的3D模型，这两种癌症每年仅在美国就导致20多万人死亡。这些模型将用于1-比较分析器官特异性如何维持，这是与癌症进展和转移直接相关的基本属性；2-确定对靶向治疗的反应是否具有器官特异性；如果是，3-器官微环境的哪些组成部分可能与器官特异性和治疗反应有关。我们假设来自免疫细胞的炎性介质 以及来自驻留的肌上皮细胞、内皮细胞和激活的基质细胞，有助于肿瘤的侵袭性和对靶向治疗的抵抗。我们将开发和利用新的生物材料、底物、定义的介质和标记，以包含免疫、内皮、正常和癌症来源的基质细胞。 这项建议汇集了细胞、分子和癌症生物学方面的专家，包括肺和乳腺肿瘤学家，以及具有成像、肿瘤免疫学、生物工程、纳米技术、材料科学和计算专业知识的研究人员。这三个项目是：i-为定义和维持正常和恶性乳腺和肺的内皮细胞表型创造条件，并确定内皮细胞对II和III中开发的模型的器官特异性反应。ii-开发正常和恶性人支气管上皮的3D模型，并测试炎症介质的影响。通过结合其他类型的细胞和炎性微环境的影响，在现有的乳腺上皮三维模型的基础上进行构建。所有项目都将测试一些靶向疗法，其中一些是由我们的合作者提供的新疗法。数据质量控制将得到确保，因为所有项目都将通过一个虚拟核心来工作，以标准化细胞培养和试剂开发，并验证标记和细胞反应的测量。生理环境的创造将有助于理解这两个不同的器官如何对各自的微环境做出反应并与之相互作用。此外，阐明乳腺和呼吸道上皮的异同将有助于发现和设计新的组织特异性 治疗。

The central objective of this proposal is to build 3D models of two epithelial cancers, lung and breast, which together cause more than 200,000 deaths each year in the U.S alone. The models will be used for 1- comparative analysis of how organ-specificity is maintained, a fundamental property that bears direct relevance to cancer progression and metastasis; 2- determining whether responses to targeted therapies are organ-specific; and if so, 3- which components of the organ microenvironment may be causally involved in organ-specificity and therapeutic response. We hypothesize that inflammatory mediators, from immune cells as well as from resident myoepithelial, endothelial and activated stromal cells, contribute to tumor aggressiveness and resistance to targeted therapies. We will develop and utilize new biomaterials, substrata, defined media and markers for inclusion of immune, endothelial and normal- and cancer-derived stromal cells. This proposal brings together experts in cell, molecular and cancer biology and includes lung and breast oncologists, and investigators with expertise in imaging, tumor immunology, bioengineering, nanotechnology, materials science and computation. The 3 projects are as follows: I- To develop conditions for defining and maintaining endothelial cell phenotypes specific to normal and malignant breast and lung, and to define organ-specific responses of endothelial cells to models developed in II and III. II- To develop a 3D model for normal and malignant human bronchial epithelium, and to test the influence of inflammatory mediators. III- To build on the existing 3D models of the breast epithelium by incorporating other cell types and the effect of inflammatory microenvironments. All projects will test a number of targeted therapeutics, some of which are new and provided by our collaborators. Data quality control will be ensured since all projects will work through a virtual core to standardize cell culture and reagent development, and validate measurements of markers' and cellular responses. The creation of a physiological milieu will aid in understanding how these two different organs respond to, and interact with, their respective microenvironments. Moreover, elucidating similarities and differences in breast and airway epithelium will facilitate discovery and design of novel tissue-specific therapies.