Breast Cancer‐Secreted DPP3 Promotes Lung Metastasis by Remodelling the Vascular Niche in Lung via the Rap1 Signalling Pathway

Metastasis is the leading cause of death related to breast cancer. Premetastatic niches (PMNs), which are remodelled by the primary tumours in distant organs, are essential for the colonisation of disseminated cancer cells. The vascular niche is among the most pivotal PMNs in breast cancer lung metastasis, and the underlying mechanism remains unclear. Here, we report that breast cancer cells secrete dipeptidyl peptidase 3 (DPP3) via small extracellular vesicles (sEVs) to promote lung metastasis. Mechanistically, circulating DPP3 upregulates RAPGEF4 to activate the Rap1 signalling pathway in the lung endothelial cells through the DPP3-PFKP-YBX1 axis and promotes angiogenesis to remodel the vascular niche, thereby increasing lung metastasis. In addition, ARF4 recognises ISGylated DPP3, which facilitates its packaging into sEVs in breast cancer cells. Finally, treatment with losartan pharmacologically inhibits the ISGylation of DPP3, preventing its secretion via sEVs. In summary, our findings demonstrate that DPP3, which is encapsulated in sEVs and secreted by breast cancer cells, regulates angiogenesis in the lung and remodels vascular niches to promote breast cancer lung metastasis, making it a potential target for the diagnosis and treatment of breast cancer metastasis.