Abstract
The tumor microenvironment, especially the extracellular matrix (ECM), is strongly associated with tumor cell proliferation and metastasis. Numerous studies have provided evidence suggesting that fibronectin (FN) in ECM supports cancer cell escape and contributes to cell migration, resulting in distant cancer metastasis and poor outcomes in patients. In our study, it was demonstrated that FN expression was elevated in tumor tissues from highly malignant NSCLC patients, compared to those with low malignancy (p = 0.0076). Importantly, FN promoted proliferative phenotypes and strengthened tumorigenesis capabilities in NSCLC cells, including A549 and Lewis cells, leading to sustained tumor growth in vivo. Mechanistically, it was identified that FN facilitated the activation of the integrin αvβ3/PI3K/AKT signaling pathway, which subsequently upregulated tumor stemness through the downstream transcription factor SOX2. Blockade of integrin αvβ3 signal efficiently suppressed NSCLC proliferation and tumorigenesis both in vitro and in vivo. In conclusion, our study demonstrated that extracellular FN could facilitate NSCLC development through the integrin αvβ3/PI3K/AKT/SOX2 signaling pathway. Blockade of integrin αvβ3 could efficiently enhance the anticancer effects of chemotherapy, offering an innovative approach for clinical NSCLC therapy.