Kumar Sandeep, Das Alakesh, Sen Shamik
WRCBB, Department of Biosciences and Bioengineering, IIT Bombay, Mumbai, India.
Mol Biosyst. 2014 Apr;10(4):838-50. doi: 10.1039/c3mb70431a. Epub 2014 Jan 31.
Epithelial to mesenchymal transition (EMT), the process during which epithelial cells lose adhesions with neighbouring cells and get converted to migratory and invasive cells, is closely tied to cancer progression. Cancer progression is also marked by increased deposition and cross linking of fibrillar extracellular matrix (ECM) proteins including collagen and fibronectin, which lead to increase in ECM density and increased cell-matrix adhesions. Thus, an imbalance between cell-matrix and cell-cell adhesions underlies cancer progression. Though several experimental studies have shown a crosstalk between cell-cell and cell-matrix adhesions, the extent to which changes in ECM density can trigger EMT via formation of cell-matrix adhesions and disassembly of cell-cell adhesions remains incompletely understood. In this paper, we have developed a computational framework for studying modulation of cell-cell adhesion by ECM density, integrating findings from multiple studies that connect ECM-mediated adhesion signaling and growth factor signaling with cell-cell adhesion. Here, we have specifically tracked changes in the levels of the E-cadherin-β catenin (Eβ) complex in response to alterations in ECM density. Our results illustrate a tug-of-war between ECM density and E-cadherin in determining Eβ levels both for a single cell as well as for a cell population, with increase in ligand density weakening cell-cell adhesions and increase in E-cadherin levels counterbalancing the effect of ECM density. Consistent with model predictions, lower levels of membrane to cytoplasmic ratios of E-cadherin were observed in MCF-7 human breast cancer cells plated on substrates with increasing collagen density. By performing simulations for a heterogeneous population consisting of both normal and EMT cells, we demonstrate that ligand density and the fraction of EMT cells collectively determine the scattering potential of a cell population. Taken together, our findings are in support of a model where increase in cell-matrix adhesions negatively regulates cell-cell adhesions thereby contributing to EMT and enhanced cellular invasion.
上皮-间质转化（EMT）是上皮细胞失去与相邻细胞的黏附并转变为迁移性和侵袭性细胞的过程，与癌症进展密切相关。癌症进展还表现为包括胶原蛋白和纤连蛋白在内的纤维状细胞外基质（ECM）蛋白的沉积和交联增加，这导致ECM密度增加和细胞-基质黏附增加。因此，细胞-基质与细胞-细胞黏附之间的失衡是癌症进展的基础。尽管多项实验研究表明细胞-细胞与细胞-基质黏附之间存在相互作用，但ECM密度的变化通过细胞-基质黏附的形成和细胞-细胞黏附的解体触发EMT的程度仍未完全了解。在本文中，我们开发了一个计算框架，用于研究ECM密度对细胞-细胞黏附的调节作用，整合了多项研究的结果，这些研究将ECM介导的黏附信号和生长因子信号与细胞-细胞黏附联系起来。在这里，我们特别追踪了E-钙黏蛋白-β连环蛋白（Eβ）复合物水平随ECM密度变化的情况。我们的结果表明，在确定单个细胞以及细胞群体的Eβ水平时，ECM密度和E-钙黏蛋白之间存在竞争关系，配体密度增加会削弱细胞-细胞黏附，而E-钙黏蛋白水平的增加会抵消ECM密度的影响。与模型预测一致，在胶原蛋白密度增加的底物上培养MCF-7人乳腺癌细胞时，观察到E-钙黏蛋白的膜与细胞质比率较低。通过对由正常细胞和EMT细胞组成的异质群体进行模拟，我们证明配体密度和EMT细胞的比例共同决定了细胞群体的散射潜力。综上所述，我们的研究结果支持这样一个模型，即细胞-基质黏附的增加会负向调节细胞-细胞黏附，从而促进EMT和增强细胞侵袭。
