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

## TL;DR

This study finds that early-onset colorectal cancer in younger adults is marked by stiffer tissues and fibrotic changes, which may drive tumor growth.

## Contribution

The study identifies biomechanical stiffening and fibrotic remodeling as novel hallmarks and potential drivers of early-onset colorectal cancer.

## Key findings

- Early-onset colorectal cancer tissues show increased stiffness, collagen changes, and elevated viscosity.
- Stromal fibrotic signatures and enhanced YAP mechanotransduction in epithelial cells are observed in early-onset colorectal cancer.
- Increased matrix stiffness in vitro promotes epithelial cell proliferation in colorectal cancer models.

## 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.

This study identifies a unique physical signature of colorectal cancer in younger adults: their tissues are mechanically stiffer than those in older patients with the same cancer. Furthermore, stromal remodeling in early‐onset colorectal cancer promotes epithelial mechanotransduction and proliferation, showing how mechanical alterations in the tissue microenvironment may drive progression of this rising disease.