ETV4 mediated tumor-associated neutrophil recruitment promotes lymphangiogenesis and lymphatic metastasis of bladder cancer

Abstract Tumor-associated neutrophils (TANs) have been reported to aid tumor cells in metastasis. However, little is known whether TANs are involved in the most common malignancy of the urinary tract, bladder cancer. Here, we find that TANs infiltration is increased in LN-metastatic BCa and is associated with poor prognosis. Neutrophil depletion results in significant reduction in popliteal LN metastasis and lymphangiogenesis. Mechanistically, transcription factor ETV4 enhances BCa cells-derived CXCL1/8 to recruit TANs, leading to the increase of VEGFA and MMP9 from TANs, and then facilitating lymphangiogenesis and LN metastasis of BCa. Moreover, phosphorylation of ETV4 at tyrosine 392 by tyrosine kinase PTK6 increases nuclear translocation of ETV4 and is essential for its function in BCa. Overall, our findings reveal a novel mechanism of how tumor cells regulate TANs-induced lymphangiogenesis and LN metastasis, and identify ETV4 as a therapeutic target of LN metastasis in BCa.