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Tumor-associated macrophages (TAMs) are the most abundant inflammatory infiltrates in the tumor microenvironment and contribute to lymph node (LN) metastasis. However, the precise mechanisms of TAMs-induced LN metastasis remain largely unknown. Herein, we identify a long noncoding RNA, termed Lymph Node Metastasis Associated Transcript 1 ( LNMAT1 ), which is upregulated in LN-positive bladder cancer and associated with LN metastasis and prognosis. Through gain and loss of function approaches, we find that  LNMAT1  promotes bladder cancer-associated lymphangiogenesis and lymphatic metastasis. Mechanistically,  LNMAT1  epigenetically activates CCL2 expression by recruiting hnRNPL to CCL2 promoter, which leads to increased H3K4 tri-methylation that ensures hnRNPL binding and enhances transcription. Furthermore,  LNMAT1 -induced upregulation of CCL2 recruits macrophages into the tumor, which promotes lymphatic metastasis via VEGF-C excretion. These findings provide a plausible mechanism for  LNMAT1 -modulated tumor microenvironment in lymphatic metastasis and suggest that  LNMAT1  may represent a potential therapeutic target for clinical intervention in LN-metastatic bladder cancer.

LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment