CAF-Driven Mechanotransduction via Collagen Remodeling Accelerates Tumor Cell Cycle Progression

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Mechanobiology

Background:

• Cancer-associated fibroblasts (CAFs) remodel the tumor microenvironment, influencing cancer progression.
• Conventional hydrogel models fail to capture the spatial heterogeneity crucial for understanding localized stiffness effects on cell behavior.

Purpose of the Study:

• To develop a novel microtissue platform to investigate how cancer-associated fibroblast-induced collagen hydrogel remodeling affects breast cancer cell proliferation.
• To elucidate the biomechanical mechanisms and signaling pathways by which localized stiffness gradients regulate cancer cell cycle progression.

Main Methods:

• Development of a collagen hydrogel microtissue platform with programmable microstrings for mechanical quantification.
• Integration of FUCCI cell cycle biosensors and molecular perturbations to monitor cell cycle and signaling.
• Real-time measurement of gel densification, stiffness changes, and pore size reduction.

Main Results:

• CAF contraction significantly increased hydrogel stiffness (350 to 775 Pa) and reduced pore diameter (5.0 to 1.9 μm).
• Increased stiffness activated YAP/TAZ nuclear translocation via collagen-integrin-actomyosin signaling, leading to a 2.4-fold increase in cancer cell proliferation.
• Pharmacological inhibition of YAP, actomyosin, or collagen reversed these effects, with partial rescue observed upon CYR61 knockdown.

Conclusions:

• Remodeled collagen hydrogels by CAFs act as critical biomechanical regulators of tumor growth.
• Targeting CAF-mediated mechanotransduction pathways presents a promising anti-cancer therapeutic strategy.