[en] Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options and treatment efficiency. Even if the latency period between asbestos exposure, the main risk factor, and mesothelioma development is very long, the local invasion of mesothelioma is very rapid leading to a mean survival of one year after diagnosis. ADAM10 (A Disintegrin And Metalloprotease) sheddase targets membrane-bound substrates and its overexpression is associated with progression in several cancers. However, nothing is known about ADAM10 implication in MPM. In this study, we demonstrated higher ADAM10 expression levels in human MPM as compared to control pleural samples and in human MPM cell line. This ADAM10 overexpression was also observed in murine MPM samples. Two mouse mesothelioma cell lines were used in this study including one primary cell line obtained by repeated asbestos fibre injections. We show, in vitro, that ADAM10 targeting through shRNA and pharmacological (GI254023X) approaches reduced drastically mesothelioma cell migration and invasion, as well as for human mesothelioma cells treated with siRNA targeting ADAM10. Moreover, ADAM10 downregulation in murine mesothelioma cells significantly impairs MPM progression in vivo after intrapleural cell injection. We also demonstrate that ADAM10 sheddase downregulation decreases the production of a soluble N-cadherin fragment through membrane N-cadherin, which stimulated mesothelioma cell migration. Taken together, we demonstrate that ADAM10 is overexpressed in MPM and takes part to MPM progression through the generation of N-cadherin fragment that stimulates mesothelioma cell migration. ADAM10 inhibition is worth considering as a therapeutic perspective in mesothelioma context.
Disciplines :
Oncology
Author, co-author :
Sepult, Christelle ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Bellefroid, Marine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Rocks, Natacha ; Université de Liège - ULiège > Département de pharmacie > Pharmacie galénique
Donati, Kim; Laboratory of Tumour and Development Biology, GIGA-cancer, Liège University, Avenue Hippocrate 13, Liège, 4000, Belgium
Gérard, Catherine ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biochimie et physiologie générales, humaines et path.
Gilles, Christine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Ludwig, Andreas; Institute of Pharmacology and Toxicology, RWTH Aachen University, Aachen, Germany
Duysinx, Bernard ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
Noël, Agnès ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Cataldo, Didier ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Bononi A, Napolitano A, Pass HI, Yang H, Carbone M. Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies. Expert Rev Respir Med. 2015;9:633–54.
Donaldson K, Poland CA, Murphy FA, Macfarlane M, Chernova T, Schinwald A. Pulmonary toxicity of carbon nanotubes and asbestos—similarities and differences. Adv Drug Deliv Rev. 2013. 10.1016/j.addr.2013.07.014.
Ray M, Kindler HL. Malignant pleural mesothelioma: an update on biomarkers and treatment. Chest. 2009;136:888–96.
Yap TA, Aerts JG, Popat S, Fennell DA. Novel insights into mesothelioma biology and implications for therapy. Nat Rev Cancer. 2017;17:475–88.
Andreini C, Banci L, Bertini I, Elmi S, Rosato A. Comparative Analysis of the ADAM and ADAMTS Families. J Proteome Res. 2005;4:881–8.
Mullooly M, Mcgowan PM, Kennedy SA, Madden SF, Crown J, Donovan NO, et al. ADAM10: a new player in breast cancer progression? Br J Cancer. 2015;113:945–51.
Fu L, Liu N, Han Y, Xie C. ADAM10 regulates proliferation, invasion, and chemoresistance of bladder cancer cells. Tumor Biol. 2014;35:9263–8.
Liu S, Zhang WEI, Liu KAI, Ji BAI, Wang G. Silencing ADAM10 inhibits the in vitro and in vivo growth of hepatocellular carcinoma cancer cells. Mol Med Rep. 2015;11:597–602.
Guo J, He L, Yuan P, Wang P, Lu Y, Tong F, et al. ADAM10 overexpression in human non-small cell lung cancer correlates with cell migration and invasion through the activation of the Notch1 signaling pathway. Oncol Rep. 2012;28:1709–18.
You B, Shan Y, Shi S, Li X, You Y. Effects of ADAM10 upregulation on progression, migration, and prognosis of nasopharyngeal carcinoma. Cancer Sci. 2015;106:1506–14.
Dreymueller D, Uhlig S, Ludwig A. DAM-family metalloproteinases in lung inflammation: potential therapeutic targets. Am J Physiol Lung Cell Mol Physiol. 2015;308:L325–43.
Pruessmeyer J, Hess FM, Alert H, Groth E, Pasqualon T, Schwarz N, et al. Leukoc require ADAM10 but Not ADAM17 their Migr Inflamm Recruit into alveolar Space. 2014;123:4077–89.
Rocks N, Paulissen G, El Hour M, Quesada F, Crahay C, Gueders M, et al. Emerging roles of ADAM and ADAMTS metalloproteinases in cancer. Biochim. 2008;90:369–79.
Paulissen G, Rocks N, Gueders MM, Crahay C, Quesada-Calvo F, Bekaert S, et al. Role of ADAM and ADAMTS metalloproteinases in airway diseases. Respir Res. 2009;10:127.
Moss ML, Stoeck A, Yan W, Dempsey PJ. ADAM10 as a target for anti-cancer therapy. Curr Pharm Biotechnol. 2008;9:2–8.
Yilmaz M, Christofori G. Mechanisms of motility in metastasizing cells. Mol Cancer Res. 2010;8:629–43.
Derycke L, Morbidelli L, Ziche M, De Wever O, Bracke M, Van Aken E. Soluble N-cadherin fragment promotes angiogenesis. Clin Exp Metastas-. 2006;23:187–201.
Paradies NE, Grunwald GB. Purification and characterization of NCAD90, a soluble endogenous form of N-cadherin, which is generated by proteolysis during retinal development and retains adhesive and neurite-promoting function. J Neurosci Res. 1993;36:33–45.
Utton MA, Eickholt B, Howell FV, Wallis J, Doherty P. Soluble N-cadherin stimulates fibroblast growth factor receptor dependent neurite outgrowth and N-cadherin and the fibroblast growth factor receptor co-cluster in cells. J Neurochem. 2001;76:1421–30.
Kim J, Islam S, Kim YJ, Prudoff RS, Sass KM, Wheelock MJ, et al. N-Cadherin extracellular repeat 4 mediates epithelial to mesenchymal transition and increased motility. J Cell Biol. 2000;151:1193–205.
Kohutek ZA, Charles G, Redpath GT, Hussaini IM. ADAM-10-ediated N-Cadherin cleavage is protein kinase C- ␣ dependent and promotes glioblastoma cell migration. J Neurosci. 2009;29:4605–15.
Yaziji H, Battifora H, Barry TS, Hwang HC, Bacchi CE, Mcintosh MW, et al. Evaluation of 12 antibodies for distinguishing epithelioid mesothelioma from adenocarcinoma: identification of a three-antibody immunohistochemical panel with maximal sensitivity and specificity. Mod Pathol. 2006;19:514–23.
Shackleton B, Crawford F, Bachmeier C. Inhibition of ADAM10 promotes the clearance of Aβ across the BBB by reducing LRP1 ectodomain shedding. Fluids Barriers CNS. 2016;13:14.
Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V, et al. A presenilin-1/g-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 2002;21:1948–56.
Reiss K, Maretzky T, Ludwig A, Tousseyn T, Strooper B De, Hartmann D, et al. ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and b-catenin nuclear signalling. EMBO J. 2005;24:742–52.
Suyama K, Shapiro I, Guttman M, Hazan RB. A signaling pathway leading to metastasis is controlled by N-cadherin and the FGF receptor. Cancer Cell. 2002;2:301–14.
Zhang W, Wu X, Wu L, Zhang W, Zhao X. Advances in the diagnosis, treatment and prognosis of malignant pleural mesothelioma. Ann Transl Med. 2015;3:182.
Huang YH, Chang PY, Wong KS, Chang CJ, Lai JY, Chen JC. An age-stratified longitudinal study of primary spontaneous pneumothorax. J Adolesc Health. 2017;61:527–32.
Schnell J, Koryllos A, Lopez-Pastorini A, Lefering R, Stoelben E. Spontaneous pneumothorax. Dtsch Arztebl Int. 2017;114:739–44.
Schuck F, Wolf D, Fellgiebel A, Endres K. Increase of alpha-Secretase ADAM10 in platelets along cognitively healthy aging. J Alzheimers Dis. 2016;50:817–26.
Kern A, Roempp B, Prager K, Walter J, Behl C. Downregulation of endogenous amyloid precursor protein processing due to cellular aging. J Biol Chem. 2006;281:2405–13.
Mezzapelle R, Rrapaj E, Gatti E, Ceriotti C, Marchis F De, Preti A. et al. Human malignant mesothelioma is recapitulated in immunocompetent BALB/c mice injected with murine AB cells. Sci Rep. 2016;6:1–12.
Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, et al. The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood. 2003;102:1186–95.
Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou C. Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling. Tumor Biol.2017;39:1–10.
Nguyen T, Mege RM. N-Cadherin and fibroblast growth factor receptors crosstalk in the control of developmental and cancer cell migrations. Eur J Cell Biol. 2016;95:415–26.
Chae YK, Ranganath K, Hammerman PS, Mohindra N, Kalyan A, Matsangou M, et al. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget. 2017;8:16052–74.
Brooks AN, Kilgour E, Smith PD. Molecular pathways: fibroblast growth factor signaling: a new therapeutic opportunity in cancer. Clin Cancer Res. 2012;18:1855–62.
Quispel-Janssen JM, Badhai J, Schunselaar L, Price S, Brammeld J, Iorio F. et al.Comprehensive pharmacogenomic profiling of malignant pleural mesothelioma identifies a subgroup sensitive to FGFR inhibition.Clin Cancer Res. 2018;24:84–94.
Moss ML, Bomar M, Liu Q, Sage H, Dempsey P, Lenhart PM, et al. The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events. J Biol Chem. 2007;282:35712–21.
Madoux F, Dreymuller D, Pettiloud J, Santos R, Ludwig A, Fields GB, et al. Discovery of an enzyme and substrate selective inhibitor of ADAM10 using an exosite-binding glycosylated substrate. Sci Rep. 2016;6:1–17.
Dreymueller D, Ludwig A. Considerations on inhibition approaches for proinflammatory functions of ADAM proteases. Platelets. 2017;28:354–61.
Vincent B. Regulation of the α-secretase ADAM10 at transcriptional, translational and post-translational levels. Brain Res Bull. 2016;126:154–69.
Altomare DA, You H, Xiao G, Ramos-nino ME, Skele KL, Rienzo A De. et al.Human and mouse mesotheliomas exhibit elevated AKT/PKB activity, which can be targeted pharmacologically to inhibit tumor cell growth. Oncogene. 2005;24:6080–9.
Altomare DA, Vaslet CA, Skele KL, Rienzo A De, Devarajan K, Jhanwar SC. et al. Priority report a mouse model recapitulating molecular features of human mesothelioma. Cancer Res. 2005;65:8090–6.
Bot J, Whitaker D, Vivian J, Lake R, Yao V, Mccauley R. Animal and in vitro models in human diseases culturing mouse peritoneal mesothelial cells. Pathol Res Pr. 2003;199:341–4.
Donati K, Sépult C, Rocks N, Blacher S, Gérard C, Noel A, et al. Neutrophil-derived interleukin 16 in premetastatic lungs promotes breast tumor cell seeding. Cancer Growth Metastas-. 2017;10:1–14.
Rocks N, Paulissen G, Quesada Calvo F, Polette M, Gueders M, Munaut C, et al. Expression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC). Br J Cancer. 2006;94:724–30.
Otjacques E, Binsfeld M, Rocks N, Blacher S, Vanderkerken K, Noel A, et al. Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors. PLoS ONE. 2013;8:e62818.
Carnet O, Lecomte J, Masset A, Primac I, Durré T, Maertens L, et al. Mesenchymal stem cells shed amphiregulin at the surface of lung carcinoma cells in a juxtacrine. NEO. 2015;17:552–63.