Escape from Homeostasis: Integrated Mathmatical and Experimental Investigation

项目摘要。 上皮细胞的行为受到我周围环境的严格控制。这种控制是通过 细胞间黏附、旁分泌/自分泌生长因子的协同作用 细胞外基质。这些机制共同确保细胞不会不适当地增殖或流浪。 从他们眼前的利基市场。致癌转化和肿瘤进展的过程需要 从这些机制中逃脱，以及肿瘤细胞群体向允许 它们变得独立于正常组织我。激活底层间质成纤维细胞，导致 增加旁分泌生长因子的产生和促进生存的ECM是发展的途径之一 肿瘤可以让我获得独立。致癌过程中宿主-肿瘤相互作用的复杂性 过程非常适合基于实验/数学的集成方法，这些方法旨在 同时处理多个变量。当前项目将初步考虑以下机制 使用三种不同的模型控制正常组织的稳态以及随后的稳态逃逸 考察物理约束、细胞-我相互作用和进化动力学在 致癌。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个

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