Tumour derived exosomal DDAH1 promotes lung aging and metastasis

Extracellular vesicles can remodel the premetastatic microenvironment of target organs by packaging various bioactive substances (including proteins and small RNA molecules) to promote tumor development and metastasis. DDAH1 is an asymmetric dimethylarginine hydrolase, which catalyzes the hydrolysis of ADMA to nitric oxide and citrulline to promote tumor development and angiogenesis. However, the role of DDAH1 carried by tumor-derived small extracellular vesicles in lung metastasis has not been reported. In this study, we revealed that tumor-derived small extracellular vesicles carry DDAH1 and promote its accumulation in the lung, facilitating the formation of the senescent matrix microenvironment in the lung and thereby affecting tumor metastasis. Overall design: To explore the effects of DDAH1 derived from breast cancer small extracellular vesicles (EVs) on mouse lung, two mouse models were constructed. The first mouse model was EVs tail vein injection mouse model. EVs derived from cultured cells were extracted and then injected into mice by tail vein injection twice a week for 5 weeks. After 5 weeks, mice were sacrificed and lung tissues were collected for gene expression profiling. The second mouse model was MDA-MB-231/DDAH1 knockout cell tumor-bearing model. MDA-MB-231/DDAH1 knockout cells were subcutaneously injected into the fourth pair of mammary glands of NSG mice to construct an orthotopic xenograft mouse model. After 5 weeks, mice were sacrificed and lung tissues were collected for gene expression profiling. The lung tissues of tumor-free mice served as a control for the lung tissues of tumor-bearing mice, which were not implanted under the fourth pair of mammary glands.