Oral Presentation 9th General Meeting of the International Proteolysis Society 2015

The Metalloprotease-Disintegrin ADAM8 modulates β1 integrin signalling and MMP activities in cancer cells and is an attractive target in tumor therapy. (#20)

Joerg W. Bartsch 1 , Catharina Conrad 1 , Garrit Koller 2 , Douglas Lauffenburger 3 , Maddy Parsons 4 , Stefanie Kramer 1 , Christopher Nimsky 1 , Uwe Schlomann 1
  1. Marburg University, Marburg, HESSEN, Germany
  2. Dental Institute , King's College London, London, United Kingdom
  3. Bioengineering, MIT , Cambridge, MA, USA
  4. Randall Institute, King's College London, London, United Kingdom

The Metalloprotease-Disintegrin ADAM8 is highly upregulated in a variety of solid tumors and ADAM8 expression is inversely correlated with patient prognosis as demonstrated for glioblastoma1, breast2 and pancreatic cancer3.  We sought to analyse the functional role of ADAM8 in solid cancers. Pancreatic cancer cells with a genetic knockdown of high endogenous ADAM8 levels or with an overexpression of ADAM8 in pancreatic cancer cells with low expression levels were generated. Migration and invasion behaviour of pancreatic cancer cells was dependent on the gene dosage of ADAM8 in these cells. In tumor cells, ADAM8 can physically interact with β1 integrin, thereby activating downstream pathways that causes activation of ERK1/2, a kinase with an essential function in pancreatic cancer. Moreover, ADAM8 regulates extracellular activities of MMP-2 and MMP-14 by a non-transcriptional mechanism. This regulation could be achieved by proteolytic cleavage of RECK (Reversion-inducing Cysteine-rich protein with Kazal Motifs), since ADAM8 expressing cells show higher levels of soluble RECK in supernatants. In addition to genetic experiments, the role of ADAM8 in pancreatic cancer was explored by pharmacological inhibitors that block ADAM8 multimerisation via binding to the ADAM8 disintegrin domain, as exemplified by a small cyclic peptide. This peptide was able to prevent tumor invasion and metastasis in an orthotopic pancreas model and led to decreased tumor load, reduced metastasis, and enhanced survival in a genetic pancreatic cancer mouse model (Median survival: 15.5 weeks for control groups vs. 24.2 weeks for peptide treated group, p<0.001). Combined with the finding that ADAM8-deficiency does not cause an apparent phenotype in mice, ADAM8 appears as an attractive target for treatment of pancreatic cancer, and due to its involvement in other cancer types, also for breast cancer and glioblastoma. 

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  3. Schlomann U, Koller G, Conrad C, Ferdous T, Golfi P, Garcia AM, Höfling S, Parsons M, Costa P, Soper R, Bossard M, Hagemann T, Roshani R, Sewald N, Ketchem RR, Moss ML, Rasmussen FH, Miller MA, Lauffenburger DA, Tuveson DA, Nimsky C, Bartsch JW. ADAM8 as a drug target in pancreatic cancer. Nat Commun. 2015 Jan 28;6:6175.