Embryogenesis, tissue repair and cancer metastasis rely on collective cell migration. In vitro studies propose that cells are stiffer while migrating in stiff substrates, but softer when plated in compliant surfaces which are typically considered as non-permissive for migration. Here we show that cells within clusters from embryonic tissue dynamically decrease their stiffness in response to the temporal stiffening of their native substrate to initiate collective cell migration. Molecular and mechanical perturbations of embryonic tissues reveal that this unexpected mechanical response involves a mechanosensitive pathway relying on Piezo1-mediated microtubule deacetylation. We further show that decreasing microtubule acetylation and consequently cluster stiffness is sufficient to trigger collective cell migration in soft non-permissive substrates. This suggests that reaching an optimal cluster-to-substrate stiffness ratio is essential to trigger the onset of this collective process. Overall, these in vivo findings challenge the current understanding of collective cell migration and its physiological and pathological roles.

胚胎发生、组织修复和癌症转移依赖于集体细胞迁移。体外研究表明，细胞在坚硬的基质中迁移时更硬，但在通常被认为不允许迁移的柔顺表面上镀层时更柔软。在这里，我们显示来自胚胎组织的簇内的细胞动态降低其刚度以响应其天然基质的时间硬化以启动集体细胞迁移。胚胎组织的分子和机械扰动表明，这种意外的机械反应涉及依赖于 Piezo1 介导的微管去乙酰化的机械敏感通路。我们进一步表明，降低微管乙酰化并因此降低簇刚度足以触发软非许可底物中的集体细胞迁移。这表明达到最佳的簇与基板刚度比对于触发该集体过程的开始至关重要。总的来说，这些体内发现挑战了目前对集体细胞迁移及其生理和病理作用的理解。