UC San Diego

Cancer cell-secreted extracellular vesicles (EVs), including exosomes, have emerged as critical effectors in the crosstalk between cancer and normal cells. Studies have shown that breast cancer-derived EVs in circulation travel to and prime lung tissue to promote formation of premetastatic niche (PMN). This process requires EV retention in lung tissue and uptake by lung residential cells. However, how EVs localized to lung tissue in vivo is poorly understood. Recent studies show that the internalization of EVs by recipient cells depends on cell-surface heparan sulfate (HS) proteoglycans (HSPGs), which vary in composition across tissues, suggesting that lung-specific HS-EV interaction may mediate EV homing to the lungs. To address this, in vitro EV uptake by lung fibroblasts with various tissue-derived HS as competitive inhibitors is measured with confocal microscopy. Whereas heparin inhibits EV uptake efficiently (IC50 around 0.12ug/ml), lung-derived HS inhibits EV uptake with much higher potency (IC50 around 0.005ug/ml) compared to heparin and HS derived from other tissues. To assess the significance of lung-specific HS in the process of EV binding to tissue environment, we treated lung tissue sections with or without heparinase and measured EV binding affinity to the slides. Not surprisingly, EV binding to lung tissue in vitro significantly relies on lung-specific HS. In future studies, we will characterize the molecular interactions between EV surface proteins and lung-derived HS that contribute to EV homing to the lungs.