Cadherin-1-mediated communication at the leader-follower boundary controls mouse breast tumor organoid collective migration

In breast tumor collective migration, a minority of tumor cells lead the group while most tumor cells follow. Leader and follower tumor cells are molecularly and functionally heterogeneous, yet communications between these cells, particularly at the leader/follower interface, promote directional movement while sustaining cohesiveness. Through 3D computational simulations and live video 3D imaging of primary mouse breast tumor organoids in a microfluidic device, we investigated the roles of type I cadherins during collective migration. Cdh1 in follower cells and Cdh3 in leader cells are both critical for collective migration. Cdh1 function at the leader/follower boundary maintains cohesivity. Cdh3 in leader cells is important for leader cell polarization. Cancer-associated fibroblasts (CAFs) co-localize with leader cells and require leader cells to enhance collective migration. Cdh11, but not Cdh2, in CAFs is important for collective migration. These findings highlight how differential cadherin-mediated communication between cells maintains organization during collective migration.