Matrix stiffness maintains bladder cancer stemness via integrin-nuclear skeleton axis.

Tumors have a unique niche system that plays an important role in their occurrence and development. At present, there is increasing interest in the biomechanical properties of niches. The increased stemness of cancer cells is closely related to bladder cancer progression and recurrence. However, how biomechanical properties in the niche regulate bladder cancer stemness remains unclear. Here, we show that as bladder cancer progresses, matrix stiffness increases, and tumor stemness increases. Mechanistically, high matrix stiffness mediates β-catenin nuclear translocation by increasing the nuclear pore size. On the other hand, it promotes the expression of the nuclear cytoskeletal protein Lamin A/C, inhibits the nuclear export of β-catenin, and finally, it upregulates the Wnt pathway to increase the stemness of cancer cells. These findings reveal a role for matrix stiffness in the regulation of stemness in bladder cancer cells and suggest that targeting matrix stiffness may be an effective strategy to delay bladder cancer progression.