Abstract Background Colitis-associated colorectal cancer (CAC) arises in inflammatory bowel disease (IBD), where chronic inflammation and fibrosis increase tissue stiffness. While stiffness is recognized in colorectal cancer, its role in IBD-CAC progression remains unclear. This study aimed to characterize biomechanical changes during IBD-CAC development and determine how stiffness drives barrier dysfunction and early neoplastic events. Methods An AOM/DSS mouse model was used to induce CAC. Disease activity, histology, and colonoscopy monitored progression. Tissue stiffness was assessed by rheometer, permeability by FITC-dextran, and epithelial/oncogenic markers by staining and Western blot. Pharmacological softening of colonic tissue was performed to evaluate the role of stiffness during disease progression. 2.5D intestinal organoid culture system on tunable polyacrylamide hydrogels (0.8 and 9.6 kPa) was performed to model the impact of matrix stiffness on epithelial cells. Results We observed a progressive increase in colonic tissue stiffness across healthy, inflamed, and dysplastic stages, correlating with collagen deposition and mucosal barrier loss. Notably, even after acute inflammation subsided (day 21), stiffness remained abnormally high, accompanied by persistent barrier dysfunction and focal dysplasia. Pharmacological softening of colonic tissue during the chronic phase significantly reduced stiffness, improved epithelial barrier integrity, and diminished nuclear accumulation of β-catenin compared with controls. These findings suggest that elevated stiffness contributes to barrier dysfunction and early neoplastic changes. In vitro, organoids cultured on stiffer matrices exhibited reduced ZO-1, Claudin-1, and E-cadherin, along with increased cell spreading and migration. Nuclear β-catenin accumulation was markedly enhanced on stiffer substrates, indicating Wnt pathway activation in response to mechanical cues. Conclusion Elevated stiffness actively drives CAC by impairing barrier function and activating oncogenic signaling. Biomechanical modulation alleviates preneoplastic changes, highlighting tissue mechanics as a therapeutic target for CAC prevention. Conflict of interest: Ms. Wang, Ziwei: No conflict of interest Xie, Ning: No conflict of interest Shu, Qiuai: No conflict of interest Cheng, Yutong: No conflict of interest Li, Yingqi: No conflict of interest Qin, Bin: No conflict of interest Shi, Haitao: No conflict of interest Cheng, Bo: No conflict of interest Li, Lu: No conflict of interest Liu, Na: No conflict of interest Xu, Feng: No conflict of interest
Wang et al. (Thu,) studied this question.