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

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