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|a dc
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|a Schlomann, Uwe
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|a Massachusetts Institute of Technology. Department of Biological Engineering
|e contributor
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|a Miller, Miles Aaron
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|a Lauffenburger, Douglas A
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|a Koller, Garrit
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|a Conrad, Catharina
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|a Ferdous, Taheera
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|a Golfi, Panagiota
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|a Garcia, Adolfo Molejon
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|a Höfling, Sabrina
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|a Parsons, Maddy
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|a Costa, Patricia
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|a Soper, Robin
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|a Bossard, Maud
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|a Hagemann, Thorsten
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|a Roshani, Rozita
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|a Sewald, Norbert
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|a Ketchem, Randal R.
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|a Moss, Marcia L.
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|a Rasmussen, Fred H.
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|a Tuveson, David A.
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|a Nimsky, Christopher
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|a Bartsch, Jörg W.
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|a Miller, Miles Aaron
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|a Lauffenburger, Douglas A
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|a ADAM8 as a drug target in pancreatic cancer
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|b Nature Publishing Group,
|c 2017-02-15T16:14:44Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/106940
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|a Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with <5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease disintegrin, are correlated with poor clinical outcome. We show that ADAM8 expression is associated with increased migration and invasiveness of PDAC cells caused by activation of ERK1/2 and higher MMP activities. For biological function, ADAM8 requires multimerization and associates with β1 integrin on the cell surface. A peptidomimetic ADAM8 inhibitor, BK-1361, designed by structural modelling of the disintegrin domain, prevents ADAM8 multimerization. In PDAC cells, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK1/2 and MMP activation. BK-1361 application in mice decreased tumour burden and metastasis of implanted pancreatic tumour cells and provides improved metrics of clinical symptoms and survival in a Kras[superscript G12D]-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.
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|a en_US
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|a Article
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|t Nature Communications
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