Editors' ChoiceCancer Immunology

Targeting metastatic NETs

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Science Signaling  16 Mar 2021:
Vol. 14, Issue 674, eabi4338
DOI: 10.1126/scisignal.abi4338

Blocking tumor-to-neutrophil cross-talk by cathepsin C may prevent lung metastasis.

Cathepsins are a family of proteases that serve critical intracellular and extracellular functions, but which are also associated with metastasis of various tumor types. Xiao et al. found that tumor-secreted cathepsin C promotes the role of neutrophils in cancer metastasis (see also coverage by Kos and de Visser). In patient samples, cathepsin C abundance in primary tumors correlated with shorter metastasis-free and overall survival in patients; its abundance in metastatic lesions was greater than that in patient-matched primary tumors; and its abundance in the serum was greater in patients with lung metastasis than in those with more distant metastases. In breast cancer cell lines, cathepsin C expression and secretion correlated with lung metastasis capacity in vivo; however, manipulating its expression had no substantial proliferative or invasive effect on the cells in culture. Analyses of various stromal cell types revealed that tumor-derived cathepsin C selectively increased the number and activation of neutrophils in the lung during the early seeding stage of metastasis. Tumor-derived cathepsin C proteolytically processed the serine protease PR3 in the membrane of cell line– and patient-derived neutrophils, which stimulated the secretion of the cytokines IL-6 and CCL3 and the production of reactive oxygen species (ROS) through branched mechanisms dependent on IL-1β. These cytokines and ROS attracted additional neutrophils and promoted the formation of neutrophil extracellular traps (NETs), respectively. The NETs facilitated the degradation of the metastasis-suppressive extracellular matrix protein TSP-1 and, consequently, the growth of lung metastases. Inhibiting cathepsin C with AZD7986 (also known as INS1007, a drug currently in trials for neutrophil-driven pulmonary diseases) or concomitantly inhibiting IL-6 and NETs inhibited neutrophil recruitment and lung metastasis of orthotopically implanted breast cancer cells in mice. In patient samples, the formation of NETs was greater among tumors of the triple-negative (TNBC) subtype, which has few treatment options. The findings detail a lung-specific, neutrophil-mediated mechanism of metastatic breast cancer and may provide new molecular targets to suppress metastatic progression in patients.

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