Here, it is demonstrated that, in response to extracellular collagen and increased ECM stiffness, polycystin‐1 interacts with disheveled‐associated activator of morphogenesis 1 (Daam1), a cytoskeletal regulator, thereby promoting microfilament remodeling, cellular protrusion formation, and enhanced motility of tumor cells through activating the RhoA signaling axis. Here, RHOA is linked to neoplasm.