Fibronectin 1 mediates pressure-induced aggressive phenotypes in colorectal cancer cells and cancer stem cells

Multiple interacting factors within the tumor microenvironment, including mechanical pressure, extracellular matrix components, hypoxia, and vascular architecture, are known to promote cancer progression. Although fibronectin 1 functions as a critical extracellular matrix glycoprotein in colorectal cancer, its specific interaction with mechanical pressure is not well characterized.

This study utilized a meta-analysis (PROSPERO: CRD42024571414) alongside an in vitro weight-induced compression model to evaluate the prognostic role of fibronectin 1 and its interaction with mechanical pressure during colorectal cancer progression.

The meta-analysis demonstrated significantly elevated fibronectin 1 expression in colorectal cancer patients compared to controls (SMD = 0.90, 95% CI: 0.56–1.25, P < 0.001) and a positive association with distant metastasis (OR = 3.63, 95% CI: 1.21–10.95, P = 0.0219). Analysis of colorectal cancer tissues versus adjacent normal tissues (n = 19) revealed markedly increased fibronectin 1 expression in both tumor cells and stromal components. Single-cell RNA sequencing analysis (GSE302903) identified FN1 expression in diverse cell populations, including cancer-associated fibroblasts, endothelial cells, macrophages, and tumor cells. Furthermore, high fibronectin 1 levels were established as a poor prognostic factor in colorectal cancer (HR = 2.47, 95% CI: 1.88–3.25, P < 0.001). In vitro experiments showed that pressure enhanced viability, proliferation, migration, and invasion of colorectal cancer cells and cancer stem cells through fibronectin 1. RNA sequencing indicated significant pressure-induced gene expression changes in colorectal cancer cells and identified the activation of multiple pathways. Specifically, the combined effect of pressure and fibronectin 1 upregulated of TGFBR1, SMAD2, SMAD4, and ROCK1 gene and p-SMAD2 expression.

The expression of fibronectin 1 predicts poor overall survival in colorectal cancer and, together with mechanical pressure, facilitates colorectal cancer progression.