2. Academic Validation
  3. Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation

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

  • Cancer Cell. 2021 Mar 8;39(3):423-437.e7. doi: 10.1016/j.ccell.2020.12.012.
Yansen Xiao 1,  Min Cong 2,  Jiatao Li 1,  Dasa He 1,  Qiuyao Wu 1,  Pu Tian 1,  Yuan Wang 1,  Shuaixi Yang 3,  Chenxi Liang 1,  Yajun Liang 1,  Jili Wen 1,  Yingjie Liu 1,  Wenqian Luo 1,  Xianzhe Lv 1,  Yunfei He 1,  Dong-Dong Cheng 4,  Tianhao Zhou 5,  Wenjing Zhao 6,  Peiyuan Zhang 1,  Xue Zhang 1,  Yichuan Xiao 1,  Youcun Qian 1,  Hongxia Wang 5,  Qiang Gao 3,  Qing-Cheng Yang 4,  Qifeng Yang 6,  Guohong Hu 7
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 2 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
  • 3 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shanghai, 200032, China.
  • 4 Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
  • 5 Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 6 Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, 250012, China.
  • 7 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. Electronic address: ghhu@sibs.ac.cn.
PMID: 33450198 DOI: 10.1016/j.ccell.2020.12.012
Abstract

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.

Keywords

Cathespin C; breast cancer; lung metastasis; metastatic niche; neutrophil; neutrophil extracellular trap.

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