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.
Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis
Disclosures: I. Sagi reported a patent (no. US 10,933,122 B2) issued. D. Schmidt-Arras reported personal fees from Mestag Therapeutics Ltd. outside the submitted work. No other disclosures were reported.
M. Müller’s present address is the Beatson Institute for Cancer Research, Glasgow, United Kingdom.
- Award Id(s): SFB841,SFB877
- Award Id(s): 57315783
- Award Id(s): F358901
- Award Id(s): 01EY1103
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Julia Bolik, Freia Krause, Marija Stevanovic, Monja Gandraß, Ilka Thomsen, Sarah-Sophie Schacht, Eva Rieser, Miryam Müller, Neele Schumacher, Jürgen Fritsch, Rielana Wichert, Eithan Galun, Juri Bergmann, Christian Röder, Clemens Schafmayer, Jan-Hendrik Egberts, Christoph Becker-Pauly, Paul Saftig, Ralph Lucius, Wulf Schneider-Brachert, Roja Barikbin, Dieter Adam, Matthias Voss, Wolfgang Hitzl, Achim Krüger, Boris Strilic, Irit Sagi, Henning Walczak, Stefan Rose-John, Dirk Schmidt-Arras; Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis. J Exp Med 3 January 2022; 219 (1): e20201039. doi: https://doi.org/10.1084/jem.20201039
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