Perturbed CD81 in lung-cancer-derived extracellular vesicles modifies its function in cancer pathophysiology

Lung cancer (LC) remains a leading cause of cancer-related fatalities, necessitating an urgent need for potent treatment strategies. This study investigates the role of extracellular vesicle (EV) cargo: CD81 in lung cancer progression and its potential as a therapeutic target. CD81 is a tetraspanin protein that has garnered considerable interest in regulating angiogenesis in various cancer types, including LC. Our study unveiled the presence of elevated levels of CD81 in EVs derived from LC cell lines and patient-derived tumoroids compared to disease-free counterparts, suggesting a potential role in cancer pathogenesis. EVs derived from CD81-silenced LC cells (EV^-siCD81) show an enhanced cellular uptake by the recipient cancer cells. More importantly, treatment with EV^-siCD81 resulted in a significant reduction in colony formation and inhibited the migratory capabilities of LC cells, suggesting therapeutic potential of CD81-bearing EVs. Notably, our study unveiled an abundance of tissue inhibitor of metalloproteinase 2 (TIMP-2) within EV^-siCD81, a key player in inhibiting matrix remodeling and promoting anti-tumoral effects in LC models. In conclusion, this study demonstrates the pivotal role of CD81 in lung cancer progression and highlights the potential of EV^-siCD81 as an innovative therapeutic agent, offering promising prospects for research and lung cancer management.