ETV4 Mediated Tumor‐Associated Neutrophil Infiltration Facilitates Lymphangiogenesis and Lymphatic Metastasis of Bladder Cancer

As a key step of tumor lymphatic metastasis, lymphangiogenesis is regulated by VEGFC‐VEGFR3 signaling pathway mediated by immune cells, mainly macrophages, in the tumor microenvironment. However, little is known whether tumor associated neutrophils are involved in lymphangiogenesis. Here, it is found 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, the 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. Tumor‐associated neutrophil (TANs) infiltration is increased in lymph node (LN)‐metastatic bladder cancer and is associated with poor prognosis. Neutrophil depletion results in significant reduction in popliteal LN metastasis and lymphangiogenesis. Mechanistically, protein tyrosine kinase 6 (PTK6)‐mediated phosphorylation of ETS variant transcription factor (ETV4) enhances bladder cancer (BCa) cells‐derived chemokine C‐X‐C motif ligand (CXCL)1/8 to recruit TANs, leading to the increase of vascular endothelial growth factor A (VEGFA) and matrix metalloproteinase‐9 (MMP9), and then facilitating lymphangiogenesis and LN metastasis of bladder cancer.