HAO1-Mediated Oxalate Metabolism Promotes Lung Pre-Metastatic Niche Formation by Inducing Neutrophil Extracellular Traps

Abstract Background Metabolic reprogramming has been shown to be involved in cancer-induced PMN formation, but the underlying mechanisms have been insufficiently explored. Methods HAO1 expression in lung tissues and alveolar epithelial cells were deteted by qPCR and Western blotting. The effect of HAO1 on the lung metastasis of cancer was investigated by orthotropic metastasis assay. Lungs and cells oxalate levels were determined using an oxalate assay kit. The effect of oxalate on neutrophil extracellular trap formation was investigated by immunofluorescence. The effect of oxalate on proliferation of breast cancer cells was revealed by immunofluorescence by colony formation assay. Results HAO1 was up-regulated in the alveolar epithelial cells of mice bearing metastatic breast cancer cells at the pre-metastatic stage. Upregulation of HAO1 led to oxalate accumulation in lung tissues and alveolar epithelial cells. Pharmacologic inhibition of HAO1 could effectively suppress the lung oxalate accumulation induced by primary cancer. Lung oxalate accumulation induced NET formation by activating NADPH oxidase. Lung oxalate accumulation promoted the proliferation of metastatic cancer cells by activating the MAPK signaling pathway. Breast cancer cells induced HAO1 expression and oxalate accumulation in alveolar epithelial cells by activating TLR3-IRF3 signaling. Conclusion These findings underscore the role of HAO1-mediated oxalate metabolism in cancer-induced lung PMN formation and metastasis. HAO1 could be an appealing therapeutic target for preventing lung metastasis of cancer.