Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation

Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung by regulating recruitment neutrophils and formation neutrophil extracellular traps (NETs). CTSC enzymatically activates membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing nuclear factor κB activation, thus upregulating IL-6 CCL3 for recruitment. In addition, CTSC-PR3-IL-1β axis induces reactive oxygen species production NETs, which degrade thrombospondin-1 support growth cancer expression secretion are associated with NET lung human tumors. Importantly, targeting compound AZD7986 effectively suppresses a mouse model. Overall, our findings reveal mechanism how regulate niches CTSC-targeting approaches treatment.