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Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Bolik, J; Krause, F; Stevanovic, M; Gandraß, M; Thomsen, I; Schacht, S-S; Rieser, E; ... Schmidt-Arras, D; + view all (2022) Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis. J Exp Med , 219 (1) , Article e20201039. 10.1084/jem.20201039. Green open access

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Abstract

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell-induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies.

Type: Article
Title: Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1084/jem.20201039
Publisher version: https://doi.org/10.1084/jem.20201039
Language: English
Additional information: © 2021 Bolik et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/)
Keywords: Innate immunity and inflammation, Solid tumors, Tumor immunology
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/10141428
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