Extracellular matrix stiffness in endometrial cancer: driving progression and modulating treatment sensitivity via the ROCK1/YAP1 axis

作者：Rui Sun, Ying Zhao, Yao Liu, Mengyao Zhang, Ziyi Qiu, Xiaohong Ma, Lina Wei, Wei Lu, Zhiming Liu, Jie Jiang · 发表于：Cell Death and Disease · 年份：2025 · DOI：10.1038/s41419-025-07697-8 · 被引用次数：17 · 研究领域：Hippo pathway signaling and YAP/TAZ、Caveolin-1 and cellular processes、Fibroblast Growth Factor Research

Endometrial cancer (EC) is among the most prevalent gynecological malignancies, with advanced or recurrent cases posing significant treatment challenges due to limited responses to conventional therapies. Growing evidence highlights the critical role of extracellular matrix (ECM) stiffness in driving tumor progression by shaping the tumor microenvironment. In this study, we demonstrate that ECM stiffness is significantly higher in EC tissues compared to normal endometrium, correlating with elevated expression of ROCK1, a mechanosensitive kinase. Using atomic force microscopy (AFM), we quantified ECM stiffness, while polyacrylamide gels with varying stiffness were employed to mimic ECM conditions in vitro. Bioinformatics analyses, immunofluorescence, Western blotting, and co-immunoprecipitation experiments revealed that ROCK1 modulates the phosphorylation of YAP1, promoting its nuclear localization and transcriptional activity, thereby driving aggressive tumor behaviors, including enhanced proliferation, migration, invasion, and reduced apoptosis. Pharmacological inhibition of ROCK1 with Y-27632 mitigated these effects, suppressing tumor growth, restoring apoptosis, and inducing cell cycle arrest. Treatment with Y-27632 improved sensitivity to chemotherapy and radiotherapy, and significantly enhanced macrophage-mediated phagocytosis, thereby boosting anti-tumor immune responses. In hormone-resistant EC cells, ROCK1 inhibition restored sensitivity to progesterone therapy. Notab...