ADAM10 mediates malignant pleural mesothelioma invasiveness

Our plain-English summary of ADAM10 mediates malignant pleural mesothelioma invasiveness, by C. Sépult, M. Bellefroid, N. Rocks, et al (Oncogene, 2019).

The study

• Authors: C. Sépult, M. Bellefroid, N. Rocks, K. Donati, C. Gérard, C. Gilles, A. Ludwig, B. Duysinx, A. Noël, D. Cataldo
• Journal: Oncogene
• Published: 2019;38(18):3521-3534
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This laboratory study examined the metalloprotease ADAM10 in malignant pleural mesothelioma (MPM). The authors compared pleural biopsies from MPM patients with control pleura (CPL) from patients explored for spontaneous pneumothorax (frozen: 6 CPL, 13 MPM; paraffin: 4 CPL, 18 MPM). ADAM10 was higher in MPM than CPL at mRNA level (P = 0.0056), protein level (P = 0.0104) and by immunohistochemistry staining score (P = 0.0429). A mouse mesothelioma cell line (PM27) was derived from ascites of mice given eight intraperitoneal injections of 400 µg crocidolite fibres every three weeks. ADAM10 was higher in mouse mesothelioma cells and tumours than in non-malignant mesothelial cells or control pleura. In mouse AB12 and PM27 cells, ADAM10 shRNA or the inhibitor GI254023X did not change proliferation or cell cycle but significantly reduced migration and invasion. In human H28 mesothelioma cells, ADAM10 siRNA reduced migration, but it did not change migration of non-malignant Met5A cells. Mice injected intrapleurally with ADAM10-depleted AB12 cells showed decreased tumour progression on bioluminescence imaging. ADAM10 depletion reduced release of a soluble 95 kDa N-cadherin fragment that stimulated migration.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining human tissue analysis, mouse mesothelioma models and in vitro cell experiments
• Who was studied: Human pleural samples (frozen: 6 control pleura, 13 MPM; paraffin-embedded: 4 control pleura, 18 MPM) from the University Hospital of Liège; male BALB/cJRj mice aged 6 to 8 weeks; mouse AB12 and PM27 and human H28 mesothelioma cell lines and non-malignant human Met5A mesothelial cells
• Exposure: Not a human exposure study; in mice, repeated intraperitoneal injections of UICC crocidolite asbestos fibres (eight injections of 400 µg, every three weeks) were used to generate primary mesothelioma; cells were otherwise exposed to ADAM10 shRNA or siRNA, the ADAM10 inhibitor GI254023X (5 µM), ionomycin and the FGFR inhibitor PD173074
• Main results:
  • ADAM10 mRNA and protein were higher in human MPM than in control pleura (mRNA P = 0.0056 for 13 MPM vs 6 CPL; protein P = 0.0104 for 13 MPM vs 5 CPL; immunohistochemistry staining score P = 0.0429 for 18 MPM vs 4 CPL)
  • In mouse AB12 and PM27 mesothelioma cells, ADAM10 shRNA did not change proliferation rates or cell cycle distribution compared with control shRNA cells
  • ADAM10 shRNA significantly decreased transwell migration of mouse AB12 and PM27 cells, delayed wound closure and decreased spheroid invasion in 3D collagen
  • The pharmacological ADAM10 inhibitor GI254023X (5 µM) reduced migration and invasion of mouse AB12 and PM27 cells without changing proliferation or cell cycle
  • After intrapleural injection of luciferase-expressing AB12 cells in mice (n = 10), ADAM10 depletion was associated with decreased tumour progression on bioluminescence imaging at 8, 15, 22 and 29 days (P < 0.01 and P < 0.001 versus both control shRNAs)
  • In human H28 mesothelioma cells, siRNA against ADAM10 significantly decreased migration in transwell and scratch assays; proliferation was not modified except a slight difference at 24 h
  • In non-malignant human Met5A mesothelial cells, ADAM10 siRNA did not change migration in transwell or scratch assays
  • ADAM10 downregulation reduced release of the soluble 95 kDa N-terminal N-cadherin fragment; conditioned medium from control AB12 cells increased AB12 migration while medium from shADAM10 cells did not, and adding recombinant N-cadherin fragment restored migration
  • The pro-migratory effect of control-cell conditioned medium was abolished by the FGFR inhibitor PD173074, and recombinant N-cadherin fragment did not overcome this inhibition
• The authors' conclusion: The authors concluded that ADAM10 is implicated in MPM progression and mediates tumour cell invasiveness via N-cadherin cleavage, and that ADAM10 inhibition is worth considering as a therapeutic perspective
• Limitations the authors state:
  • The control pleura and MPM patient groups differed in age and could not be age-matched, so part of the difference in ADAM10 expression might relate to ageing
  • The authors stated that further studies are needed to assess whether this mechanism could be targeted with ADAM10 inhibitors

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Latency, Asbestos Exposure, Mesothelioma.

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