Bioengineering 3-D Models for Breast Cancer Therapy

这项提议的中心目标是建立两种上皮性癌症的3D模型，肺癌和乳腺癌，这两种癌症每年仅在美国就导致超过20万人死亡。这些模型将用于1-器官特异性如何维持的比较分析，这是与癌症进展和转移直接相关的基本特性；2-确定对靶向治疗的反应是否具有器官特异性；如果是这样，器官微环境的哪些成分可能与器官特异性和治疗反应有因果关系。我们假设炎症介质来自免疫细胞

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.