TIMP-1 triggers neutrophil extracellular trap formation in pancreatic cancer

Tumor-derived protein tissue inhibitor of metalloproteinases-1 (TIMP-1) correlates with poor prognosis in many cancers, including highly lethal pancreatic ductal adenocarcinoma (PDAC). The non-canonical signaling activity of TIMP-1 is emerging as one basis for its contribution to cancer progression. However, TIMP-1-triggered progression-related biological processes are largely unknown. Formation of neutrophil extracellular traps (NET) in the tumor microenvironment is known to drive progression of PDAC, but factors or molecular mechanisms initiating NET formation in PDAC remain elusive. In this study, gene set enrichment analysis of a human PDAC proteome dataset revealed that TIMP-1 protein expression most prominently correlates with neutrophil activation in patient-derived tumor tissues. TIMP-1 directly triggered formation of NETs in primary human neutrophils, which was dependent on the interaction of TIMP-1 with its receptor CD63 and subsequent ERK signaling. In genetically engineered PDAC-bearing mice, TIMP-1 significantly contributed to NET formation in tumors, and abrogation of TIMP-1 or NETs prolonged survival. In patient-derived PDAC tumors, NETs predominantly colocalized with areas of elevated TIMP-1 expression. Furthermore, TIMP-1 plasma levels correlated with DNA-bound myeloperoxidase, a NET marker, in the blood of PDAC patients. A combination of plasma levels of TIMP-1 and NETs with the clinically established marker CA19-9 allowed improved identification of prognostically distinct PDAC patient subgroups. These observations may have a broader impact, since elevated systemic levels of TIMP-1 are associated with the progression of a wide range of neutrophil-involved inflammatory diseases.