During collective migration of epithelial cells, the migration direction is aligned over a tissue-scale expanse. Although the collective cell migration is known to be directed by mechanical forces transmitted via cell-cell junctions, it remains elusive how the intercellular force transmission is coordinated with intracellular biochemical signaling to achieve collective movements. Here, we show that intercellular coupling of extracellular signal-regulated kinase (ERK)-mediated mechanochemical feedback yields long-distance transmission of guidance cues. Mechanical stretch activates ERK through epidermal growth factor receptor (EGFR) activation, and ERK activation triggers cell contraction. The contraction of the activated cell pulls neighboring cells, evoking another round of ERK activation and contraction in the neighbors. Furthermore, anisotropic contraction based on front-rear polarization guarantees unidirectional propagation of ERK activation, and in turn, the ERK activation waves direct multicellular alignment of the polarity, leading to long-range ordered migration. Our findings reveal that mechanical forces mediate intercellular signaling underlying sustained transmission of guidance cues for collective cell migration.

在上皮细胞的集体迁移过程中，迁移方向在组织尺度的范围内对齐。尽管已知集体细胞迁移是由经由细胞-细胞连接处传递的机械力指导的，但是如何将细胞间力传递与细胞内生化信号传递协调以实现集体运动仍不清楚。在这里，我们显示细胞外信号调节激酶（ERK）介导的机械化学反馈的细胞间偶联产生指导信号的长距离传输。机械拉伸通过表皮生长因子受体（EGFR）激活激活ERK，而ERK激活则触发细胞收缩。活化细胞的收缩拉动邻近细胞，引起邻近细胞的另一轮ERK活化和收缩。此外，基于前后极化的各向异性收缩可确保ERK激活的单向传播，进而，ERK激活波可指导极性的多细胞排列，从而导致远距离有序迁移。我们的发现揭示了机械力介导了指导信号的持续传递，从而促进了细胞集体迁移。