Girdin/GIV regulates collective cancer cell migration by controlling cell adhesion and cytoskeletal organization

Pathological observations show that cancer cellsfrequently invade the surrounding stroma in collective groups rather than through single cell migration. Here, we studied the role of the actin-binding proteinGirdin, a specific regulator of collective migration of neuroblastsin the brain, in collective cancer cellmigration. We found that Girdin was essential for the collective migration of the skin cancercell line A431 on collagen gels as well as their fibroblast-led collective invasion in an organotypic culture model. We provide evidence that Girdin binds to β-catenin that plays important roles in the Wnt signaling pathwayand in E- cadherin-mediated cell- cell adhesion. Girdin-depleted cells displayed scattering and impaired E- cadherin-specific cell- cell adhesion. Importantly, Girdin depletion led to impaired cytoskeletal association of the β-catenin complex, which was accompanied by changes in the supracellular actin cytoskeletal organization of cancer cellcohorts on collagen gels. Although the underlying mechanism is unclear, this observation is consistent with the established role of the actin cytoskeletal system and cell- cell adhesionin the collective behaviorof cells. Finally, we showed the correlation of the expression of Girdin with that of the components of the E- cadherincomplex and the differentiation of human skin cancer. Collectively, our results suggest that Girdin is an important modulator of the collective behaviorof cancer cells.