Department of Biomedical Engineering, Yale University, New Haven, CT 06520.
Yale Systems Biology Institute, Yale University, West Haven, CT 06516.
Proc Natl Acad Sci U S A. 2017 Jul 11;114(28):E5750-E5759. doi: 10.1073/pnas.1700054114. Epub 2017 Jun 27.
Cell polarization and directional cell migration can display random, persistent, and oscillatory dynamic patterns. However, it is not clear whether these polarity patterns can be explained by the same underlying regulatory mechanism. Here, we show that random, persistent, and oscillatory migration accompanied by polarization can simultaneously occur in populations of melanoma cells derived from tumors with different degrees of aggressiveness. We demonstrate that all of these patterns and the probabilities of their occurrence are quantitatively accounted for by a simple mechanism involving a spatially distributed, mechanochemical feedback coupling the dynamically changing extracellular matrix (ECM)-cell contacts to the activation of signaling downstream of the Rho-family small GTPases. This mechanism is supported by a predictive mathematical model and extensive experimental validation, and can explain previously reported results for diverse cell types. In melanoma, this mechanism also accounts for the effects of genetic and environmental perturbations, including mutations linked to invasive cell spread. The resulting mechanistic understanding of cell polarity quantitatively captures the relationship between population variability and phenotypic plasticity, with the potential to account for a wide variety of cell migration states in diverse pathological and physiological conditions.
细胞极化和定向细胞迁移可以表现出随机的、持续的和振荡的动态模式。然而，目前尚不清楚这些极性模式是否可以用相同的基础调节机制来解释。在这里，我们表明，在源自侵袭性不同的肿瘤的黑色素瘤细胞群体中，随机的、持续的和振荡的迁移伴随着极化可以同时发生。我们证明，所有这些模式及其发生的概率都可以通过一种简单的机制来定量解释，该机制涉及一个空间分布的、机械化学反馈，将动态变化的细胞外基质（ECM）-细胞接触与 Rho 家族小 GTP 酶下游信号的激活耦合起来。该机制得到了预测性数学模型和广泛的实验验证的支持，并可以解释不同细胞类型的先前报道的结果。在黑色素瘤中，这种机制还解释了遗传和环境扰动的影响，包括与侵袭性细胞扩散相关的突变。对细胞极性的机制理解定量地捕捉了群体变异性和表型可塑性之间的关系，有可能解释在不同病理和生理条件下广泛的细胞迁移状态。
