Introduction

Cancer metastasis is associated with increased cancer incidence, recurrence, and mortality. The role of cell contact guidance behaviors in cancer metastasis has been recognized but has not been elucidated yet.

Methods

The contact guidance behavior of cancer cells in response to topographical constraints is identified using microgrooved substrates with varying dimensions at the mesoscopic scale. Then, the cell morphology is determined to quantitatively analyze the effects of substrate dimensions on cells contact guidance. Cell density and migrate velocity signatures within the cellular population are determined using time-lapse phase-contrast microscopy. The effect of soluble factors concentration is determined by culturing cells upside down. Then, the effect of cell-substrate interaction on cell migration is investigated using traction force microscopy.

Results

With increasing depth and decreasing groove width, cell elongation and alignment are enhanced, while cell spreading is inhibited. Moreover, cells display preferential distribution on the ridges, which is found to be more pronounced with increasing depth and groove width. Determinations of cell density and migration velocity signatures reveal that the preferential distribution on ridges is caused by cell upward migration. Combined with traction force measurement, we find that migration toward ridges is governed by different cell-substrate interactions between grooves and ridges caused by geometrical constraints. Interestingly, the upward migration of cells at the mesoscopic scale is driven by entropic maximization.

Conclusions

The mesoscopic cell contact guidance mechanism based on the entropic force driven theory provides basic support for the study of cell alignment and migration along healthy tissues with varying size, thereby aiding in the prediction of cancer metastasis.

Graphical Abstract

中文翻译：

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接触引导驱动细胞在介观尺度上向上迁移

介绍

癌症转移与癌症发病率、复发率和死亡率的增加有关。细胞接触引导行为在癌症转移中的作用已被认识，但尚未阐明。

方法

使用介观尺度上具有不同尺寸的微槽基底来识别癌细胞响应于地形限制的接触引导行为。然后，确定细胞形态以定量分析基底尺寸对细胞接触引导的影响。使用延时相差显微镜测定细胞群内的细胞密度和迁移速度特征。可溶性因子浓度的影响通过倒置培养细胞来确定。然后，使用牵引力显微镜研究细胞-基质相互作用对细胞迁移的影响。

结果

随着深度的增加和凹槽宽度的减小，细胞伸长和排列得到增强，同时细胞铺展受到抑制。此外，细胞在脊上显示出优先分布，随着深度和凹槽宽度的增加，这种分布更加明显。细胞密度和迁移速度特征的测定表明，脊上的优先分布是由细胞向上迁移引起的。结合牵引力测量，我们发现向脊的迁移是由几何约束引起的凹槽和脊之间不同的细胞-基质相互作用控制的。有趣的是，细胞在介观尺度上的向上迁移是由熵最大化驱动的。

结论

基于熵力驱动理论的细观细胞接触引导机制为研究细胞沿着不同大小的健康组织排列和迁移提供了基础支持，从而有助于预测癌症转移。

图形概要