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Schoeps, B.* ; Eckfeld, C.* ; Prokopchuk, O.* ; Böttcher, J.* ; Häußler, D.* ; Steiger, K.* ; Demir, I.E.* ; Knolle, P.* ; Soehnlein, O.* ; Jenne, D. ; Hermann, C.D.* ; Krüger, A.*

Timp1 triggers neutrophil extracellular trap formation in pancreatic cancer.

Cancer Res. 81, 3568-3579 (2021)
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Tumor-derived protein tissue inhibitor of metalloproteinases-1 (TIMP1) correlates with poor prognosis in many cancers, including highly lethal pancreatic ductal adenocarcinoma (PDAC). The noncanonical signaling activity of TIMP1 is emerging as one basis for its contribution to cancer progression. However, TIMP1-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 TIMP1 protein expression most prominently correlates with neutrophil activation in patientderived tumor tissues. TIMP1 directly triggered formation of NETs in primary human neutrophils, which was dependent on the interaction of TIMP1 with its receptor CD63 and subsequent ERK signaling. In genetically engineered PDAC-bearing mice, TIMP1 significantly contributed to NET formation in tumors, and abrogation of TIMP1 or NETs prolonged survival. In patient-derived PDAC tumors, NETs predominantly colocalized with areas of elevated TIMP1 expression. Furthermore, TIMP1 plasma levels correlated with DNA-bound myeloperoxidase, a NET marker, in the blood of patients with PDAC. A combination of plasma levels of TIMP1 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, because elevated systemic levels of TIMP1 are associated with the progression of a wide range of neutrophil-involved inflammatory diseases.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Tissue Inhibitor; Tumor; Cd63; Metalloproteinase-1; Cells
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Journal Cancer Research
Quellenangaben Volume: 81, Issue: 13, Pages: 3568-3579 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place Philadelphia, Pa.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Lung Health and Immunity (LHI)
Grants German Center of Infection Research (DZIF)
Wilhelm Sander-Stiftung, Munich, Germany
Deutsche Forschungsgemeinschaft, Bonn, Germany