Bioengineering 3-D Models for Organ-Specific Cancer Therapy in Lung and Breast

这项提议的中心目标是建立两种上皮性癌症-肺癌和乳腺癌的3D模型，这两种癌症 加在一起，仅在美国每年就有超过20万人死亡。这些模型将用于1- 对器官特异性如何维持的比较分析，这是一种直接影响 与癌症进展和转移的相关性；2-确定对靶向治疗的反应是否 器官特异性；如果是，3-器官微环境的哪些成分可能与 器官特异性和治疗反应。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 对靶向治疗的进攻性和抵抗力。我们将开发和利用生物新材料， 包括免疫、内皮细胞、正常和癌症来源的底物、定义的介质和标记物 基质细胞。 这项提案汇集了细胞、分子和癌症生物学方面的专家，包括肺癌和乳腺癌。 肿瘤学家和具有成像、肿瘤免疫学、生物工程、纳米技术专业知识的研究人员， 材料科学和计算。这3个项目如下：i-为界定和 维持正常和恶性乳腺和肺部特异的内皮细胞表型，并确定 血管内皮细胞对II和III中开发的模型的器官特异性反应II-开发用于 正常和恶性人支气管上皮，并检测炎性介质的影响。Iiito 通过合并其他类型的细胞来构建现有的乳房上皮3D模型，以及 炎性微环境。所有项目都将测试一些靶向疗法，其中一些是 新的，由我们的合作者提供。由于所有项目都将运行，因此将确保数据质量控制 通过虚拟核心来标准化细胞培养和试剂开发，并验证 标志物和细胞的反应。创造一个生理环境将有助于理解这些 两个不同的器官对各自的微环境做出反应，并与之相互作用。此外，澄清 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. IIITo 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 tissuespecific therapies.