Deciphering Stiffness-Driven Changes in Colorectal Cancer by Proteomics

Tumor stiffening plays a pivotal role in cancer progression. Increased tumor stiffness, resulting from interactions between cancer cells and their surrounding microenvironment, alters the tumor's mechanical properties and significantly impacts cancer growth and metastasis, the primary cause of cancer-related death. Despite the importance of tumor stiffness, systematic studies exploring its effect on protein dysregulation are limited. In this study, focused on colorectal cancer, we show by in-depth proteomics that matrix stiffness significantly alters the expression of secreted proteins, while intracellular protein levels remain largely unaffected. Functional assays reveal that the changes observed by proteomics in the secretome, driven by matrix stiffness, enhance cell migration, angiogenesis, and matrix remodeling, which collectively would contribute to a more aggressive cancer phenotype in a real scenario. Our findings emphasize the critical role of matrix stiffness in driving colorectal cancer progression through changes in the secretome, offering valuable insights for the development of biomechanical cancer therapies.