Escape from Homeostasis: Integrated Mathmatical and Experimental Investigation

项目摘要。 上皮细胞的行为受到周围微环境的严格调控。 细胞-细胞粘附、旁分泌/自分泌生长因子的协调作用，以及通过粘附到 细胞外基质这些机制共同确保细胞不会不适当地增殖或偏离 从他们的直接利基。致癌转化和肿瘤进展的过程需要 逃避这些机制，以及肿瘤细胞群向允许 它们变得不依赖于正常组织的微环境。激活底层基质成纤维细胞， 旁分泌生长因子和促生存细胞外基质的增加是发展的一种方式， 肿瘤可以实现mE独立性。致癌性肿瘤中宿主-肿瘤相互作用的复杂性 过程本身很适合于基于实验/数学的综合方法，这些方法旨在 同时处理多个变量。目前的项目将首先考虑各种机制， 通过使用三种不同的建模来控制正常组织的稳态和随后的稳态逃逸 研究物理约束，细胞-mE相互作用和进化动力学在 致癌作用在第二部分中，我们将使用新的体外器官型细胞培养模型来测试 激活的基质的存在可以提供第二种

Project Summary. Epithelial cell behavior is tightly regulated by the surrounding mE. This control is mediated through the coordinated actions of cell-cell adhesion, paracrine/autocrine growth factors and through adhesion to the extracellular matrix. Together, these mechanisms ensure that cells do not proliferate inappropriately or stray from their immediate mE niche. The process of oncogenic transformation and tumor progression entails the escape from these mechanisms, and the evolution ofthe tumor cell population towards phenotypes that allow them to become independent ofthe normal tissue mE. Activation ofthe underlying stromal fibroblasts, leading to the increased production of paracrine growth factors and pro-survival ECM is one way that developing tumors can achieve mE independence. The complexity of the host-tumor interaction in the carcinogenic process lends itself well to integrated experimental/mathematical based approaches, which are designed to handle multiple variables simultaneously. The current project will initially consider the mechanisms which control normal tissue homeostasis and subsequently homeostatic escape by using three different modeling approaches that examine the roles physical constraints, cell-mE interactions and evolutionary dynamics play in carcinogenesis. In the second part we will use novel in vitro organotypic cell culture models to test whether the presence of an activated stroma can provide the second