Cell-mediated matrix deformations and cell-cell adhesions determine epithelial collective cell migration phenotypes

Area of Science:

• Cell biology
• Developmental biology
• Biophysics

Background:

• Tissue development relies on collective cell migration phenotypes like rotational (acinar structures) and invasive (duct-like structures).
• The mechanisms controlling these distinct cell migration patterns during epithelial morphogenesis, such as tubulogenesis, remain poorly understood.
• P-cadherin (CDH3) and cell-matrix interactions are implicated in cell migration but their specific roles in phenotype switching are unclear.

Purpose of the Study:

• To investigate how P-cadherin (CDH3) and mechanical cell-matrix interactions influence rotational versus invasive collective cell migration phenotypes during tubulogenesis.
• To elucidate the role of CDH3 in the transition between migration phenotypes and its impact on matrix deformation.
• To determine if RhoA activation can rescue the invasive migration phenotype in CDH3-depleted cells.

Main Methods:

• Utilized a custom 3D microfluidic assay for live-cell imaging of wild-type (WT) and CDH3-depleted (CDH3-/-) epithelial cysts during tubulogenesis.
• Simultaneously measured matrix deformation rates and observed cell-matrix interactions, including focal adhesions.
• Manipulated RhoA signaling to assess its effect on CDH3-deficient cells.

Main Results:

• WT epithelial cysts initially exhibit rotational phenotypes and transition to invasive phenotypes for tubulogenesis.
• Invasive collective migration (ICM) phenotypes correlate with higher matrix deformation rates than rotational phenotypes.
• CDH3 is essential for the transition to ICM phenotypes, with its depletion decreasing matrix deformation rates.
• Loss of CDH3 impairs ICM, but this can be rescued by RhoA activation, which increases matrix deformation and vinculin recruitment.

Conclusions:

• CDH3 plays a critical role in enabling epithelial cysts to switch from rotational to invasive migration phenotypes during tubulogenesis.
• Mechanical cell-matrix interactions, particularly matrix deformation rates, are key regulators of collective cell migration phenotypes.
• RhoA signaling is a downstream effector that can restore invasive migration in CDH3-deficient cells, highlighting its importance in regulating cell-matrix dynamics and tissue morphogenesis.