Xiao Yating, Jiang Yingying, Bao Ting, Hu Xin, Wang Xiang, Han Xiaoning, Deng Linhong
Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou 213164, China.
School of Pharmacy, Changzhou University, Changzhou 213164, China.
Gels. 2025 Aug 13;11(8):642. doi: 10.3390/gels11080642.
Cancer-associated fibroblasts (CAFs) restructure collagen hydrogels via actomyosin-driven fibril bundling and crosslinking, increasing polymer density to generate mechanical stress that accelerates tumor proliferation. Conventional hydrogel models lack spatial heterogeneity, thus obscuring how localized stiffness gradients regulate cell cycle progression. To address this, we developed a collagen hydrogel-based microtissue platform integrated with programmable microstrings (single/double tethering), enabling real-time quantification of gel densification mechanics and force transmission efficiency. Using this system combined with FUCCI cell cycle biosensors and molecular perturbations, we demonstrate that CAF-polarized contraction increases hydrogel stiffness (350 → 775 Pa) and reduces pore diameter (5.0 → 1.9 μm), activating YAP/TAZ nuclear translocation via collagen-integrin-actomyosin cascades. This drives a 2.4-fold proliferation increase and accelerates G1/S transition in breast cancer cells. Pharmacological inhibition of YAP (verteporfin), actomyosin (blebbistatin), or collagen disruption (collagenase) reversed mechanotransduction and proliferation. Partial rescue upon CYR61 knockdown revealed compensatory effector networks. Our work establishes CAF-remodeled hydrogels as biomechanical regulators of tumor growth and positions gel-based mechanotherapeutics as promising anti-cancer strategies.
癌症相关成纤维细胞（CAFs）通过肌动球蛋白驱动的原纤维束集和交联来重构胶原水凝胶，增加聚合物密度以产生加速肿瘤增殖的机械应力。传统的水凝胶模型缺乏空间异质性，因此掩盖了局部刚度梯度如何调节细胞周期进程。为了解决这个问题，我们开发了一种基于胶原水凝胶的微组织平台，该平台集成了可编程微丝（单/双系链），能够实时定量凝胶致密化力学和力传递效率。使用该系统结合FUCCI细胞周期生物传感器和分子扰动，我们证明CAF极化收缩增加了水凝胶刚度（350→775帕斯卡）并减小了孔径（5.0→1.9微米），通过胶原-整合素-肌动球蛋白级联激活YAP/TAZ核转位。这使乳腺癌细胞的增殖增加了2.4倍，并加速了G1/S期转换。对YAP（维替泊芬）、肌动球蛋白（布列他汀）或胶原破坏（胶原酶）的药理学抑制逆转了机械转导和增殖。CYR61基因敲低后的部分挽救揭示了补偿效应网络。我们的工作将CAF重塑的水凝胶确立为肿瘤生长的生物力学调节因子，并将基于凝胶的机械疗法定位为有前景的抗癌策略。
