Mathematical Modeling Reveals That Changes to Local Cell Density Dynamically Modulate Baseline Variations in Cell Growth and Drug Response.
Mathematical Modeling Reveals That Changes to Local Cell Density Dynamically Modulate Baseline Variations in Cell Growth and Drug Response.
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DOI：
10.1158/0008-5472.can-15-3232
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发表时间：
2016-05-15
期刊：
影响因子：
11.2
通讯作者：
Lavi O
中科院分区：
文献类型：
--
作者：
Greene JM;Levy D;Herrada SP;Gottesman MM;Lavi O
细胞间的变异会导致耐药性，从而导致癌症治疗失败。已经开发出监测肿瘤异质性的实验技术，但细胞间变异的估计通常无法解释细胞生长过程中预期的时空变异。为了充分捕捉这种动态变化的程度，我们开发了一个由卵巢癌细胞系体外实验支持的机械数学模型。我们引入了动态基线细胞间变异的概念，展示了一个细胞群新兴的时空异质性如何归因于局部细胞密度和细胞周期的差异。对癌细胞几何排列和空间密度的操纵表明，给定固定的整体细胞密度，仅根据细胞运动和局部条件就可以观察到生长、增殖和紫杉醇诱导的细胞凋亡率的显着差异。我们的结论是，对异质性水平变化的任何统计估计都应该与基线系统的动态和空间效应相结合。这种方法结合了实验和理论方法来系统地分析生物现象，值得考虑作为细胞生物学研究的基本参考模型，研究影响癌细胞行为的动态过程。
Cell-to-cell variations contribute to drug resistance with consequent therapy failure in cancer. Experimental techniques have been developed to monitor tumor heterogeneity, but estimates of cell-to-cell variation typically fail to account for the expected spatiotemporal variations during the cell growth process. To fully capture the extent of such dynamic variations, we developed a mechanistic mathematical model supported by in vitro experiments with an ovarian cancer cell line. We introduce the notion of dynamic baseline cell-to-cell variation, showing how the emerging spatiotemporal heterogeneity of one cell population can be attributed to differences in local cell density and cell-cycle. Manipulation of the geometric arrangement and spatial density of cancer cells revealed that given a fixed global cell density, significant differences in growth, proliferation, and paclitaxel-induced apoptosis rates were observed based solely on cell movement and local conditions. We conclude that any statistical estimate of changes in the level of heterogeneity should be integrated with the dynamics and spatial effects of the baseline system. This approach incorporates experimental and theoretical methods to systematically analyze biological phenomena, and merits consideration as an underlying reference model for cell biology studies that investigate dynamic processes affecting cancer cell behavior.