ADAM8 as a drug target in pancreatic cancer

Schlomann, Uwe; Koller, Garrit; Conrad, Catharina; Ferdous, Taheera; Golfi, Panagiota; Garcia, Adolfo Molejon; Höfling, Sabrina; Parsons, Maddy; Costa, Patricia; Soper, Robin; Bossard, Maud; Hagemann, Thorsten; Roshani, Rozita; Sewald, Norbert; Ketchem, Randal R.; Moss, Marcia L.; Rasmussen, Fred H.; Miller, Miles A.; Lauffenburger, Douglas A.; Tuveson, David A.; Nimsky, Christopher; Bartsch, Jörg W.

doi:10.1038/ncomms7175

Cited by 96 publications

(119 citation statements)

References 59 publications

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“…4B). ADAM8 and ADAM10 exhibit overlapping substrate spectra, as exemplified by cleavage of CD23 (36), while ADAM8 expression in mouse skin is strongly up-regulated in the absence of ADAM10 (37). We speculated that ADAM8 might likewise compensate for the loss of ADAM10 in myeloid cells, but observed similar sIL-6R serum levels in ADAM8 knock-out mice as compared to wild type animals (Fig.…”

Section: Adam17 Is the Major Sheddase Of Pma-and Lps-induced Il-6r Shmentioning

confidence: 78%

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles

Schumacher

Meyer

Mauermann

et al. 2015

Journal of Biological Chemistry

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121

117

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Background:A soluble form of IL-6 receptor mediates pathogenic IL-6 trans-signaling. Results: ADAM10 and ADAM17 release IL-6 receptor from both human and murine monocytes/macrophages, whereas in the blood IL-6 receptor is also present on microvesicles. Conclusion: Shedding of endogenous IL-6 receptor is similar in humans and mice. Significance: Microvesicle release represents a novel mode of soluble IL-6 receptor generation with potential clinical implications.

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Section: Adam17 Is the Major Sheddase Of Pma-and Lps-induced Il-6r Shmentioning

confidence: 78%

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles

Schumacher

Meyer

Mauermann

et al. 2015

Journal of Biological Chemistry

Self Cite

121

117

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“…In tumor cells, ADAM8 is implicated in interactions with β1-integrin and ADAM8- dependent FAK and ERK1/2 activation. In a mouse model of PDAC, recent studies using an ADAM8 inhibitor have demonstrated a marked reduction in tumor load, infiltration, and metastasis in vivo (148). …”

Section: Adams and Gastrointestinal Cancermentioning

confidence: 99%

ADAM Proteases and Gastrointestinal Function

Jones¹,

Rustagi

Dempsey³

2016

Annu. Rev. Physiol.

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A disintegrin and metalloproteinases (ADAMs) are a family of cell surface proteases that regulate diverse cellular functions, including cell adhesion, migration, cellular signaling, and proteolysis. Proteolytically active ADAMs are responsible for ectodomain shedding of membrane-associated proteins. ADAMs rapidly modulate key cell signaling pathways in response to changes in the extracellular environment (e.g., inflammation) and play a central role in coordinating intercellular communication within the local microenvironment. ADAM10 and ADAM17 are the most studied members of the ADAM family in the gastrointestinal tract. ADAMs regulate many cellular processes associated with intestinal development, cell fate specification, and the maintenance of intestinal stem cell/progenitor populations. Several signaling pathway molecules that undergo ectodomain shedding by ADAMs [e.g., ligands and receptors from epidermal growth factor receptor (EGFR)/ErbB and tumor necrosis factor α (TNFα) receptor (TNFR) families] help drive and control intestinal inflammation and injury/repair responses. Dysregulation of these processes through aberrant ADAM expression or sustained ADAM activity is linked to chronic inflammation, inflammation-associated cancer, and tumorigenesis.

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“…Based on structural modeling of the disintegrin domain of ADAM8, Schlomann et al 90 synthesized a 6-amino acid cyclic peptide, designated BK-1361 that prevented multimerization and thus activation of the ADAM8. BK-1361 was found to inhibit ADAM8-dependent cell adhesion and block proteolysis of the ADAM8 substrate, CD23.…”

Section: Adam8 As a Target For Cancer Treatmentmentioning

confidence: 99%

The ADAMs family of proteases as targets for the treatment of cancer

Mullooly

McGowan

Crown

et al. 2016

Cancer Biology & Therapy

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The ADAMs (a disintegrin and metalloproteases) are transmembrane multidomain proteins implicated in multiple biological processes including proteolysis, cell adhesion, cell fusion, cell proliferation and cell migration. Of these varied activities, the best studied is their role in proteolysis. However, of the 22 ADAMs believed to be functional in humans, only approximately a half possess matrix metalloproteinase (MMP)-like protease activity. In contrast to MMPs which are mostly implicated in the degradation of extracellular matrix proteins, the main ADAM substrates are the ectodomains of type I and type II transmembrane proteins. These include growth factor/cytokine precursors, growth factor/cytokine receptors and adhesion proteins. Recently, several different ADAMs, especially ADAM17, have been shown to play a role in the development and progression of multiple cancer types. Consistent with this role in cancer, targeting ADAM17 with either low molecular weight inhibitors or monoclonal antibodies was shown to have anticancer activity in multiple preclinical systems. Although early phase clinical trials have shown no serious side effects with a dual ADAM10/17 low molecular weight inhibitor, the consequences of long-term treatment with these agents is unknown. Furthermore, efficacy in clinical trials remains to be shown.

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ADAM8 as a drug target in pancreatic cancer

Cited by 96 publications

References 59 publications

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles

Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles

ADAM Proteases and Gastrointestinal Function

The ADAMs family of proteases as targets for the treatment of cancer

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