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

The incidence of sporadic early onset colorectal cancer (EO CRC, under 50 years of age) is rising rapidly, yet the causes behind such rise remain poorly understood. Epidemiological studies indicate that lifestyle and environmental exposures may result in chronic inflammation, which is known to trigger tissue fibrosis. We hypothesized that fibrotic remodeling and biomechanical stiffening of colorectal tissues represent hallmarks and drivers of EO CRC. Using primary human tissues, we show that EO CRC is associated with changes in collagen microstructure, increased stiffness and elevated viscosity of primary tumors. Spatial profiling and immunostaining reveal pro-fibrotic transcriptional programs in stromal cells, alongside enhanced mechanotransduction and proliferation in epithelial cells. In vitro, increased matrix stiffness promotes increased 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.