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Locally advanced and metastatic invasive bladder cancer ( BC ) has a poor prognosis, and no advanced therapies beyond cisplatin‐based combination chemotherapy have been developed. Therefore, it is an urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive  BC  for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and  CRK  in a formation of premetastatic niches and subsequent metastases.  CRK  adaptors were overexpressed in invasive  UM ‐ UC ‐3  BC  cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of  UM ‐ UC ‐3 cells were completely abolished by  CRK  elimination. Mass spectrometry analysis identified that ErbB2 was contained in  UM ‐ UC ‐3‐derived exosomes in a  CRK ‐dependent manner; the exosomes significantly increased proliferation and invasion properties of low‐grade 5637  BC  cells and  HUVEC s through  FAK  and  PI 3K/ AKT  signaling pathways. In athymic mice educated with  UM ‐ UC ‐3‐derived exosomes, i.v. implanted  UM ‐ UC ‐3 cells were trapped with surrounding  PKH 67‐labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from  CRK ‐depleted  BC  cells failed to induce these malignant features. Taken together, we showed that  CRK  adaptors elevated the expression of ErbB2/3 in  BC  cells, and these tyrosine kinase/adaptor units were transferred from host  BC  cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus,  CRK  intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic  BC .

Exosomes containing ErbB2/ CRK induce vascular growth in premetastatic niches and promote metastasis of bladder cancer