# Cell clusters softening triggers collective cell migration in vivo

## TL;DR

Cells in embryonic tissues become softer to initiate collective migration when their environment stiffens, challenging previous assumptions about cell stiffness and movement.

## Contribution

The study identifies a mechanosensitive pathway involving Piezo1 and microtubule deacetylation that triggers collective cell migration in vivo.

## Key findings

- Cells within clusters soften in response to substrate stiffening to initiate collective migration.
- Piezo1-mediated microtubule deacetylation is essential for this mechanical response.
- Reducing cluster stiffness enables migration in soft, non-permissive substrates.

## Abstract

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.

Collective cell migration in embryonic tissues is triggered by cell softening due to a microtubule deacetylation pathway involving the mechanosensitive ion channel Piezo1.