Biomechanical Mechanisms of Oncogenic Epithelial to Mesenchymal Transition

致癌上皮向间质转化的生物力学机制

• 批准号: 1134201
• 负责人: Samir Ghadiali
• 金额: $ 35万
• 依托单位: Ohio State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1134201&HistoricalAwards=false
• 关键词: Biomechanical; Mechanisms; Oncogenic; Epithelial; Mesenchymal

1134201GhadialiCancer is a major cause of death in the United States. Although uncontrolled cell division is a hallmark of tumor formation, the spread of cancer cells from a primary tumor to other organs, i.e. metastasis, is the key feature that leads to high mortality rates. During metastasis, epithelial cancer cells detach from the primary tumor site and acquire a highly motile and/or mesenchymal phenotype. Migration/invasion of these cells into surrounding tissue and the circulatory/lymphatic system leads to colonization of distal tissues and secondary tumor formation. The central biological mechanism responsible for metastasis is known as epithelial to mesenchymal transition (EMT). In addition to its role in cancer metastasis, EMT is a fundamental biological process that plays an important role in embryonic development, wound healing and organ fibrosis. During EMT polarized epithelial cells undergo dramatic biochemical and biostructural changes and acquire a mesenchymal phenotype with enhanced migratory and invasive capacity. Although many of the biochemical signaling events that occur during oncogenic EMT are known, the biomechanical mechanisms governing oncogenic EMT are not well established. Furthermore, although it is well established that the tumor microenvironment can influence cancer progression and that increased tumor stiffness is a diagnostic indicator of advanced disease, there is limited information about how changes in the tumor?s biomechanical properties (i.e. matrix stiffness) influence EMT and metastatic potential.This proposal utilizes a combination of biophysical, molecular biology and quantitative engineering tools to investigate the biomechanical mechanisms governing oncogenic EMT and to investigate how changes tissue/matrix mechanics influences EMT and metastasis. Sophisticated experimental techniques will be used to characterize changes in cellular mechanics during EMT in different cancer cells. Several biomechanical markers of EMT (i.e. stiffness, viscoelasticity and contractility) will be correlated with cell migration and invasion behaviors. In addition to establishing a unique set of biomechanical markers of EMT, these studies will also provide an innovative way to quantitatively assess metastatic potential based on the cell's mechanical phenotype. Experimental techniques will also be used to investigate how changes in substrate/matrix stiffness influence the biomechanical and biochemical signaling mechanisms responsible for oncogenic EMT. Finally, three-dimensional multi-scale computational models of tumor cell detachment and migration/invasion will be developed and these computational models will be used to develop new insights into how changes in cell mechanics may be used to mitigate metastasis. The proposed research studies will provide training for a post-doctoral research scientist and undergraduate/graduate students in biomedical engineering at The Ohio State University and will also be integrated into an undergraduate course in quantitative physiology. Outreach activities included contributing to a summer educational program for high school students in computational modeling hosted by the Ohio Supercomputer Center.

1134201 Ghadiali癌症是美国的主要死因。虽然不受控制的细胞分裂是肿瘤形成的标志，但癌细胞从原发性肿瘤扩散到其他器官，即转移，是导致高死亡率的关键特征。在转移过程中，上皮癌细胞从原发肿瘤部位脱离并获得高度运动和/或间充质表型。这些细胞迁移/侵入周围组织和循环/淋巴系统，导致远端组织定植和继发性肿瘤形成。负责转移的中心生物学机制被称为上皮间质转化（EMT）。除了在癌症转移中的作用外，EMT是一种基本的生物学过程，在胚胎发育、伤口愈合和器官纤维化中起重要作用。在EMT极化上皮细胞经历戏剧性的生化和生物结构的变化，并获得增强的迁移和侵袭能力的间充质表型。虽然致癌EMT过程中发生的许多生化信号事件是已知的，但控制致癌EMT的生物力学机制还没有很好地建立。此外，尽管已经确定肿瘤微环境可以影响癌症进展，并且肿瘤硬度增加是晚期疾病的诊断指标，但关于肿瘤微环境如何变化的信息有限。本研究综合运用生物物理学、分子生物学和定量工程学的方法，探讨肿瘤发生EMT的生物力学机制，以及组织/基质力学的变化对EMT和转移的影响。复杂的实验技术将用于表征不同癌细胞EMT期间细胞力学的变化。EMT的几种生物力学指标（即刚度、粘弹性和收缩性）将与细胞迁移和侵袭行为相关。除了建立一套独特的EMT生物力学标志物外，这些研究还将提供一种基于细胞机械表型定量评估转移潜力的创新方法。实验技术也将被用来研究如何在基板/基质刚度的变化影响的生物力学和生化信号机制负责致癌EMT。最后，将开发肿瘤细胞脱离和迁移/侵袭的三维多尺度计算模型，这些计算模型将用于开发细胞力学变化如何用于减轻转移的新见解。拟议的研究将为俄亥俄州州立大学生物医学工程的博士后研究科学家和本科生/研究生提供培训，并将纳入定量生理学的本科课程。外联活动包括为俄亥俄州超级计算机中心主办的高中生计算建模暑期教育方案作出贡献。