Matrix stiffness drives squamous cell carcinoma progression via a Piezo1-mediated mechanotransduction feedback loop

作者：Zixi Jiang, Yantao Xu, Yanru Wang, Zhuxin Dong, Wenjihao Hu, Juan Su, Lisha Wu, Yi He, Lin Zhu, Dan Jian, Jiachen Liu, Hui Li, Zeyu Chen, Xiang Chen, Shuang Zhao · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.10.041 · 被引用次数：9 · 研究领域：Erythrocyte Function and Pathophysiology、Cancer Cells and Metastasis、Cellular Mechanics and Interactions

• This work provides the first demonstration that increased matrix stiffness promotes SCC proliferation and invasion through the Piezo1-RCC2 (non-Hippo)-YAP signaling axis. • Our study reveals firstly that matrix stiffness-induced activation of Piezo1 in tumor cells can remodel fibroblasts via a paracrine mechanism, further enhancing matrix stiffness and establishing a positive feedback loop that exacerbates SCC progression. • This research establishes the inaugural evidence that Piezo1 serves as the pivotal mechano-decoder translating biomechanical cues into clinical outcomes, with its expression level independently predicting DFS in cutaneous SCC patients. Squamous cell carcinoma (SCC) is one of the most frequent solid tumor accounting for more than one million cancer deaths annually. Emerging evidence highlights the critical role of mechanical signaling in tumor progression, yet the mechanobiological interplay between extracellular matrix (ECM) stiffness and SCC pathogenesis remains poorly understood. This study aimed to investigate how matrix stiffness drives SCC progression via Piezo1-mediated mechanotransduction and its clinical implications. Atomic force microscopy quantified tissue stiffness in human cutaneous, oral, and lung SCC samples. Spatial transcriptomics and single-cell RNA sequencing (scRNA-seq) analyzed ECM- and mechanoreceptor-related gene expression. In vitro models using tunable-stiffness gels assessed SCC cell proliferation, invasion, and Piezo1/YAP acti...