Quantitative Analysis of Tumor Cell Migration in Three Dimensioinal Matrices

我们研究的目的是对肿瘤转移有一个定量的认识。由于细胞迁移是转移的核心部分，我们正在开发定量实验和计算方法来研究三维基质中的迁移。我们的初步研究表明，癌细胞在二维和三维基质中的迁移有显著差异。现有的二维分析方法无法研究基质结构和力学的影响以及蛋白水解酶的胞外降解。这种对关键过程和变量信息的缺乏导致了不完整和不准确的理解。我们的目标是通过量化肿瘤细胞在原生三维环境中的迁移来纠正这些问题。在拟议的研究中，我们将发展对肿瘤细胞迁移的系统级理解。细胞粘附、基质组成、基质结构和蛋白水解的个体和集体作用将在成熟的前列腺癌细胞系中进行研究。这将通过以下具体目标来实现：1)量化整合素和细胞外基质在调节三维肿瘤细胞运动中的系统相互作用；2)量化细胞外基质结构对肿瘤细胞蛋白酶活性的影响；3)建立多尺度计算模型来预测和量化细胞在三维基质中的粘附和迁移。我们对抗和治愈癌症的能力取决于我们对调节转移过程的理解。本建议中概述的项目将是在达到这种理解水平方面迈出的重要一步。通过结合实验和模拟，在模拟体内设置的受控环境中进行，我们将能够量化基质和细胞在肿瘤细胞迁移中的个体和集体作用。通过我们的实验和模拟实现的系统级量化将作为发现抗癌治疗的平台。首席研究员/项目主任：Zaman， Muhammad H.，博士。

The goal of our studies is to develop a quantitative understanding of tumor metastasis. As cell migration is the central part of metastasis, we are developing quantitative experimental and computational methods to study migration in three dimensional matrices. Our preliminary studies have indicated that cancer cell migration in two and three dimensional matrices is significantly different. The effects of matrix structure and mechanics as well as extracellular degradation by proteolytic enzymes can not be studied in existing two dimensional assays. This lack of information about key processes and variables leads to incomplete and inaccurate understanding. Our goal is to rectify these problems by quantifying tumor cell migration in native like three dimensional environments. In the proposed studies, we will develop a system level understanding of tumor cell migration. The individual and collective roles of cell adhesion, matrix composition, matrix structure and proteolysis will be studied in well established prostate cancer cell lines. This will be accomplished through the following specific aims: 1) Quantify the systematic interactions of integrins and extracellular matrix in regulating three -dimensional tumor cell motility, 2) Quantify the effects of extracellular matrix structure on protease activity in tumor cells and 3) Develop multi-scale computational models to predict and quantify cell adhesion and migration in three dimensional matrices. Our ability to combat and cure cancer rests on our understanding of the processes regulating metastasis. The project outlined in this proposal will be a significant step in reaching that level of understanding. By combining experiments and simulations, carried out in controlled environments that mimic in vivo settings, we will be able to quantify the individual and collective roles of matrix and cells in tumor cell migration. The systems level quantification achieved through our experiments and simulation will serve as a platform for discovery of anti- cancer therapeutics. Principal Investigator/Program Director : Zaman, Muhammad H., Ph.D..