Escape from Homeostasis: Integrated Mathmatical and Experimental Investigation

逃离稳态：综合数学和实验研究

• 批准号: 8555187
• 负责人: Alexander Robertson Allan Anderson
• 金额: $ 45.74万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8555187
• 关键词: Acceleration; Adhesions; Architecture; Attention; Cancer Biology; Cell Culture Techniques; Cell Line; Cell Polarity; Cell-Cell Adhesion; Cells; Computer Simulation; Development; E-Cadherin; Ensure; Epithelial; Epithelial Cells; Equilibrium; Esophagus; Evolution; Extracellular Matrix; Fibroblasts; Game Theory; Growth; Growth Factor; Heterogeneity; Homeostasis; Human; Hybrids; Image; In Vitro; Investigation; Lesion; Mediating; Melanoma Cell; Methods; Microscopy; Modeling; Normal tissue morphology; Oncogenes; Oncogenic; PI3K/AKT; Pathway interactions; Phenotype; Play; Population; Premalignant; Process; Production; Proliferating; Research; Role; Route; Signal Transduction; System; Technology; Testing; Tight Junctions; Tissues; autocrine; base; cancer prevention; cancer therapy; carcinogenesis; cell behavior; cell motility; design; host neoplasm interaction; keratinocyte; mathematical model; models and simulation; neoplastic cell; novel; operation; paracrine; pressure; protein expression; treatment strategy; tumor; tumor progression

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.

项目摘要。 上皮细胞的行为受到周围 mE 的严格调节。这种控制是通过 细胞间粘附、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过度增殖或偏离 来自他们直接的 ME 利基。致癌转化和肿瘤进展的过程需要 逃离这些机制，以及肿瘤细胞群向表型的进化，使得 它们变得独立于正常组织mE。激活底层基质成纤维细胞，导致 增加旁分泌生长因子和促生存 ECM 的产生是发展 肿瘤可以实现 mE 独立性。致癌过程中宿主与肿瘤相互作用的复杂性 该过程非常适合基于实验/数学的综合方法，这些方法旨在 同时处理多个变量。当前的项目将首先考虑以下机制： 通过使用三种不同的模型来控制正常组织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其中所起的作用的方法 致癌作用。在第二部分中，我们将使用新型体外器官型细胞培养模型来测试是否 活化基质的存在可以为上皮细胞的转化提供第二次“打击” 通过逐步引入激活癌基因来永生化。研究的最后部分将 整合我们对稳态的理解来开发可能需要新方法的稳态控制方法 实验和理论发展。我们期望对稳态逃逸有更深入的了解 就宿主与肿瘤的相互作用而言，将对癌症预防和新治疗产生重大影响 策略。与 PS-OC 中的其他项目一样，项目 1 建立在紧密联系的研究范式之上。 将数学模型与经验观察相结合。拟议的研究很大程度上依赖于 成像（主要是显微镜）作为将癌症生物学与数学联系起来的使能技术 模型。与其他项目一样，我们将密切关注从数据中提取信息的准确性。 图像并批判性地检查成像集成在告知模型参数和 与模型模拟预测的系统动力学进行比较。