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 活化的基质的存在可以在上皮细胞的转化中提供第二次“打击”， 通过逐步引入激活的癌基因而得以永生。研究的最后一部分将 整合我们对体内平衡的理解，开发出体内平衡控制的方法，这可能需要新的 实验和理论的发展。我们希望对稳态逃逸有更深入的了解， 就宿主-肿瘤相互作用而言，将对癌症预防和新的治疗产生重大影响 战略布局与PS-OC中的其他项目一样，项目1建立在研究范式的基础上， 将数学建模与经验观察相结合。拟议的研究严重依赖于 成像（主要是显微镜）作为使能技术，将癌症生物学与数学 模型与其他项目一样，我们将密切关注从 图像和批判性地检查成像的集成在通知模型参数的限制， 与通过模型模拟预测的系统动态相比。

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 "hit" in the transformation of epithelial cells that have been immortalized using the step-wise introduction of activating oncogenes. The final part of the study will integrate our understanding of homeostasis to develop methods for homeostatic control that may require new experimental and theoretical developments. We expect that a deeper understanding of homeostatic escape, in terms of host-tumor interactions, will have major implications for cancer prevention and novel treatment strategies. As with the other projects in the PS-OC, Project 1 is built on the research paradigm that closely integrates mathematical modeling with empirical observations. The proposed research relies heavily on imaging (primarily microscopy) as the enabling technology that bridges cancer biology with the mathematical models. As in the other projects, we will pay close attention to the accuracy of information extraction from the images and critically examine the limits of the integration of imaging in informing model parameters and comparing to system dynamics predicted by model simulations.