Table 1. Model systems for collective cell migration and identified roles of Rho GTPases.

Model	Type of collective migration	Biological and/or application context	Roles of Rho GTPases	References
Cell-sheet migration (2D, in vitro)	Migration of cohesive cells as 2D monolayer in vitro	Simplified model for epithelial and/or endothelial cell migration, wound healing	Rac, Rho in leading cells: DDR1/Rho axis reduces actomyosin contractility and stabilizes cell-cell junctions; sheet migration requires p114RhoGEF-dependent myosin II contractility	47,49,136,137
Convergent extension movement (2D in vivo)	Migration of multilayered cell sheets	Gastrulation	Wnt-driven Rac and Rho engagement controlling filopodia, protrusion, polarity and protrusion lifespan	138,139
Tubulogenesis (3D, in vitro, in vivo)	Epithelial collective sprouting and tube formation, including lumen formation.	Morphogenesis, gland development (mammary, salivary, kidney)	Rac-dependent multicellular budding tip composed of several positionally instable leader cells followed by positionally stable cells forming the duct with inner lumen and outward basement membrane deposition; Rho-dependent restriction of leader cells. Rac-dependent maintenance of cell-cell adhesion	54,110,115,140
Invasion of collective strands (3D, in vitro)	Finger-like sprouting of multicellular strand	Epithelial tubulogenesis, vascular sprouting, strand-like cancer cell invasion	Low Rho activity stabilizes cell-cell junction; active Rho favors conversion to single-cell migration	83,103
Tumor explant invasion (3D, in vitro)	3D invasion	Cancer, personalized medicine	Rac-dependent leader cell selection; Rho dependent engagement of heterologous leader cells (fibroblasts); silencing of Rho along cell-cell junctions	62,83,141