Biomechanical Phenotyping Reveals Unique Mechanobiological Signatures of Early‐Onset Colorectal Cancer

Abstract While both incidence and mortality of sporadic average‐onset colorectal cancer (AO CRC, above 50 years of age) are in constant decline, sporadic early‐onset colorectal cancer (EO CRC, under 50 years of age) is rising rapidly. Yet, the causes behind this rise remain poorly understood. Epidemiological studies indicate that lifestyle and environmental exposures may result in chronic inflammation, which is known to trigger tissue fibrosis. This study tests the hypothesis that fibrotic remodeling and biomechanical stiffening of colorectal tissues represent measurable hallmarks and potential drivers of EO CRC. Using primary human tissues, this work shows that EO CRC is associated with changes in collagen microstructure, increased stiffness, and elevated viscosity of primary tumors. Spatial transcriptional profiling and immunostaining reveal pro‐fibrotic signatures in stromal cells, alongside enhanced Yes‐associated protein (YAP) mechanotransduction and proliferation in epithelial cells of EO CRC tissues. Mechanistically, increasing matrix stiffness in vitro promotes proliferation of epithelial cells in 2D and 3D colorectal cancer models. Together, these findings establish EO CRC as a disease marked by early and widespread biomechanical remodeling, suggesting that a fibrotic and stiffened tissue microenvironment may orchestrate EO CRC tumor initiation.