ADAM8 As a Drug Target in Pancreatic Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2015 Jan 29

PMID 25629724

Citations 55

Authors

Uwe Schlomann

Garrit Koller

Catharina Conrad

Taheera Ferdous

Panagiota Golfi

Adolfo Molejon Garcia

Sabrina Hofling

Maddy Parsons

Patricia Costa

Robin Soper

Maud Bossard

Thorsten Hagemann

Rozita Roshani

Norbert Sewald

Randal R Ketchem

Marcia L Moss

Fred H Rasmussen

Miles A Miller

Douglas A Lauffenburger

David A Tuveson

Christopher Nimsky

Jorg W Bartsch

Affiliations

Soon will be listed here.

Abstract

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(G12D)-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.

Citing Articles

The long non-coding RNA NEAT1 contributes to aberrant STAT3 signaling in pancreatic cancer and is regulated by a metalloprotease-disintegrin ADAM8/miR-181a-5p axis.

Gao Y, Zandieh K, Zhao K, Khizanishvili N, Di Fazio P, Yu X Cell Oncol (Dordr). 2024; .

PMID: 39412616 DOI: 10.1007/s13402-024-01001-0.

Extracellular Release of a Disintegrin and Metalloproteinase Correlates With Periodontal Disease Severity.

Aljohmani A, Heinze H, Gharzia F, Reda B, Abdrabou A, Becker S J Clin Periodontol. 2024; 52(2):237-248.

PMID: 39317350 PMC: 11743067. DOI: 10.1111/jcpe.14073.

Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma.

Evers M, Stuhmer T, Schreder M, Steinbrunn T, Rudelius M, Jundt F Blood Cancer J. 2024; 14(1):156.

PMID: 39261477 PMC: 11390935. DOI: 10.1038/s41408-024-01133-4.

Prognostic value of a disintegrin and metalloproteinase Domain-8 in heart failure.

Ji Z, Guo J, Xu Y, Zuo W, Zhang R, Carvalho A Heliyon. 2024; 10(11):e32072.

PMID: 38912460 PMC: 11190534. DOI: 10.1016/j.heliyon.2024.e32072.

Blockade of the ADAM8-Fra-1 complex attenuates neuroinflammation by suppressing the Map3k4/MAPKs axis after spinal cord injury.

Qian Z, Li R, Zhao T, Xie K, Li P, Li G Cell Mol Biol Lett. 2024; 29(1):75.

PMID: 38755530 PMC: 11100242. DOI: 10.1186/s11658-024-00589-3.

References

Janes P, Saha N, Barton W, Kolev M, Wimmer-Kleikamp S, Nievergall E . Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell. 2005; 123(2):291-304. DOI: 10.1016/j.cell.2005.08.014. View

Murphy G . The ADAMs: signalling scissors in the tumour microenvironment. Nat Rev Cancer. 2008; 8(12):929-41. DOI: 10.1038/nrc2459. View

Romagnoli M, Mineva N, Polmear M, Conrad C, Srinivasan S, Loussouarn D . ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis. EMBO Mol Med. 2013; 6(2):278-94. PMC: 3927960. DOI: 10.1002/emmm.201303373. View

Lewis J, Schwartz M . Mapping in vivo associations of cytoplasmic proteins with integrin beta 1 cytoplasmic domain mutants. Mol Biol Cell. 1995; 6(2):151-60. PMC: 275825. DOI: 10.1091/mbc.6.2.151. View

Rao H, Lu G, Kajiya H, Garcia-Palacios V, Kurihara N, Anderson J . Alpha9beta1: a novel osteoclast integrin that regulates osteoclast formation and function. J Bone Miner Res. 2006; 21(10):1657-65. PMC: 1937336. DOI: 10.1359/jbmr.060718. View

Grippo P, Fitchev P, Bentrem D, Melstrom L, Dangi-Garimella S, Krantz S . Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice. Gut. 2012; 61(10):1454-64. DOI: 10.1136/gutjnl-2011-300821. View

Naus S, Reipschlager S, Wildeboer D, Lichtenthaler S, Mitterreiter S, Guan Z . Identification of candidate substrates for ectodomain shedding by the metalloprotease-disintegrin ADAM8. Biol Chem. 2006; 387(3):337-46. DOI: 10.1515/BC.2006.045. View

Kelly K, Hutchinson G, Nebenius-Oosthuizen D, Smith A, Bartsch J, Horiuchi K . Metalloprotease-disintegrin ADAM8: expression analysis and targeted deletion in mice. Dev Dyn. 2004; 232(1):221-31. DOI: 10.1002/dvdy.20221. View

Blobel C . ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol. 2005; 6(1):32-43. DOI: 10.1038/nrm1548. View

10.

Guaiquil V, Swendeman S, Zhou W, Guaiquil P, Weskamp G, Bartsch J . ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice. J Mol Med (Berl). 2010; 88(5):497-505. PMC: 2862722. DOI: 10.1007/s00109-010-0591-8. View

11.

Schlomann U, Wildeboer D, Webster A, Antropova O, Zeuschner D, Knight C . The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion. J Biol Chem. 2002; 277(50):48210-9. DOI: 10.1074/jbc.M203355200. View

12.

Shields M, Dangi-Garimella S, Redig A, Munshi H . Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression. Biochem J. 2011; 441(2):541-52. PMC: 8215985. DOI: 10.1042/BJ20111240. View

13.

Liu J, Ben Q, Yao W, Zhang J, Chen D, He X . BMP2 induces PANC-1 cell invasion by MMP-2 overexpression through ROS and ERK. Front Biosci (Landmark Ed). 2012; 17(7):2541-9. DOI: 10.2741/4069. View

14.

Schlomann U, Yamamoto S, Jockusch H, Bartsch J . Tumor necrosis factor alpha induces a metalloprotease-disintegrin, ADAM8 (CD 156): implications for neuron-glia interactions during neurodegeneration. J Neurosci. 2000; 20(21):7964-71. PMC: 6772711. View

15.

Valkovskaya N . Hypoxia-dependent expression of ADAM8 in human pancreatic cancer cell lines. Exp Oncol. 2008; 30(2):129-32. View

16.

Fritzsche F, Jung M, Xu C, Rabien A, Schicktanz H, Stephan C . ADAM8 expression in prostate cancer is associated with parameters of unfavorable prognosis. Virchows Arch. 2006; 449(6):628-36. DOI: 10.1007/s00428-006-0315-1. View

17.

Mochizuki S, Okada Y . ADAMs in cancer cell proliferation and progression. Cancer Sci. 2007; 98(5):621-8. PMC: 11160018. DOI: 10.1111/j.1349-7006.2007.00434.x. View

18.

Zhang R, Yuan Y, Zuo J, Liu W . Prognostic and clinical implication of a disintegrin and metalloprotease 8 expression in pediatric medulloblastoma. J Neurol Sci. 2012; 323(1-2):46-51. DOI: 10.1016/j.jns.2012.07.040. View

19.

Wildeboer D, Naus S, Sang Q, Bartsch J, Pagenstecher A . Metalloproteinase disintegrins ADAM8 and ADAM19 are highly regulated in human primary brain tumors and their expression levels and activities are associated with invasiveness. J Neuropathol Exp Neurol. 2006; 65(5):516-27. DOI: 10.1097/01.jnen.0000229240.51490.d3. View

20.

Miller M, Barkal L, Jeng K, Herrlich A, Moss M, Griffith L . Proteolytic Activity Matrix Analysis (PrAMA) for simultaneous determination of multiple protease activities. Integr Biol (Camb). 2010; 3(4):422-38. PMC: 3173501. DOI: 10.1039/c0ib00083c. View