2021/01/14 by Yansen Xiao, Min Cong, Jiatao Li +24 · 2 citations
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Immune cells in cancer #Neutrophil, Myeloperoxidase and Oxidative Mechanisms #S100 Proteins and Annexins
paper · doi:10.1016/j.ccell.2020.12.012
openalex publication_date 2021/01/14 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/29
Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.