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

Area of Science:

• Oncology
• Biomedical Engineering
• Cell Biology

Background:

• Tumor microenvironments play a critical role in cancer development.
• Biomechanical properties of the tumor niche are gaining attention.
• Increased cancer stemness correlates with bladder cancer progression and recurrence.

Purpose of the Study:

• To investigate how biomechanical properties of the tumor niche regulate bladder cancer stemness.
• To elucidate the mechanisms by which matrix stiffness influences cancer stemness.

Main Methods:

• Analysis of matrix stiffness and cancer stemness in progressing bladder tumors.
• Investigation of the role of matrix stiffness in regulating beta-catenin (β-catenin) nuclear translocation.
• Assessment of Lamin A/C expression and its effect on β-catenin nuclear export.
• Evaluation of Wnt pathway activation in response to matrix stiffness.

Main Results:

• Matrix stiffness increases as bladder cancer progresses, correlating with increased tumor stemness.
• High matrix stiffness promotes β-catenin nuclear translocation by increasing nuclear pore size.
• Increased matrix stiffness upregulates Lamin A/C, inhibiting β-catenin nuclear export and activating the Wnt pathway.
• These events collectively enhance bladder cancer stemness.

Conclusions:

• Matrix stiffness is a key regulator of stemness in bladder cancer cells.
• The findings reveal a novel mechanism linking matrix stiffness to Wnt pathway activation and cancer stemness.
• Targeting matrix stiffness presents a potential therapeutic strategy to impede bladder cancer progression.