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Inhibition of BMP2 and BMP4 represses Barrett’s esophagus while enhancing the regeneration of squamous epithelium in preclinical models

  • Author Footnotes
    # shared co-first authorship
    Ana C.P. Correia
    Correspondence
    Correspondence to: Ana C. P. Correia, Center of Experimental and Molecular Medicine, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands;
    Footnotes
    # shared co-first authorship
    Affiliations
    Center of Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
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  • Author Footnotes
    # shared co-first authorship
    Danielle Straub
    Footnotes
    # shared co-first authorship
    Affiliations
    Center of Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
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  • Matthew Read
    Affiliations
    Department of Surgery, St Vincent’s Hospital, Melbourne, Victoria, Australia,

    Department of Surgery, The University of Melbourne, St Vincent’s Hospital, Melbourne, Victoria, Australia
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  • Sanne J.M. Hoefnagel
    Affiliations
    Center of Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
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  • Salvador Romero-Pinedo
    Affiliations
    Biomedical Research Centre, CIBM, Institute of Biomedicine and Regenerative Investigation, IBIMER, University of Granada, Granada, Spain

    Department of Biochemistry and Molecular Biology III and Immunology, University of Granada, Granada, Spain
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  • Ana C. Abadía-Molina
    Affiliations
    Biomedical Research Centre, CIBM, Institute of Biomedicine and Regenerative Investigation, IBIMER, University of Granada, Granada, Spain

    Department of Biochemistry and Molecular Biology III and Immunology, University of Granada, Granada, Spain
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  • Nicholas J. Clemons
    Affiliations
    Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

    Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia
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  • Kenneth Wang
    Affiliations
    Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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  • Silvia Calpe
    Affiliations
    Center of Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands

    Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands
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  • Wayne Phillips
    Affiliations
    Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia

    Cancer Biology and Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
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  • Kausilia K. Krishnadath
    Correspondence
    Correspondence to: Sheila K. Krishnadath, MD, PhD; Laboratory of Experimental Medicine and Paediatrics, Antwerp University, Universiteitsplein 1, 2610 Antwerp, Belgium, ; Tel +31 614291955
    Affiliations
    Department of Gastroenterology and Hepatology, Antwerp University Hospital, Belgium;

    Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Belgium
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  • Author Footnotes
    # shared co-first authorship
Open AccessPublished:January 24, 2023DOI:https://doi.org/10.1016/j.jcmgh.2023.01.003
Inhibition of BMP2 and BMP4 represses Barrett’s esophagus while enhancing the regeneration of squamous epithelium in preclinical models
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      Abstract

      Background and Aim

      Barrett’s esophagus is considered to be an metaplastic lesion that predisposes for esophageal adenocarcinoma. Development of Barrett’s esophagus is considered to be driven by sonic hedgehog (SHH) mediated bone morphogenetic protein (BMP) signaling. We aimed to investigate in preclinical in vivo models if targeting canonical BMP signaling could be an effective treatment for Barrett’s esophagus.

      Methods and Results

      Selective inhibition of BMP2 and BMP4 within an in vivo organoid model of Barrett’s esophagus inhibited development of columnar Barrett’s cells, while favoring expansion of squamous cells. Silencing of Noggin, a natural antagonist of BMP2, BMP4 and BMP7, in a conditional knockout mouse model, induced expansion of a Barrett’s-like neo-columnar epithelium from multi-lineage glands. Conversely, in this model specific inhibition of BMP2 and BMP4 led to the development of a neo-squamous lineage. In an ablation model, inhibition of BMP2 and BMP4 resulted in the regeneration of neo-squamous epithelium after the cryoablation of columnar epithelium at the squamo-columnar junction. Through lineage tracing the generation of the neo-squamous mucosa was found to originate from K5+ progenitor squamous cells.

      Conclusions

      Here we demonstrate that specific inhibitors of BMP2 and BMP4 attenuates the development of Barrett’s columnar epithelium, providing a novel potential strategy for the treatment of Barrett’s esophagus and the prevention of esophageal adenocarcinoma.

      Graphical abstract

      Figure thumbnail fx1
      Graphical Abstract

      Keywords

      Abbreviations:

      BE (Barrett’s esophagus), BMP (Bone Morphogenetic Protein), DGERD (duodeno-gastro-esophageal reflux disease), EAC (esophageal adenocarcinoma), PPI (Proton Pump Inhibition), SCJ (Squamous-columnar junction), SHH (Sonic hedgehog), SQ (squamous), TGF-β (transforming growth factor-beta)

      Article info

      Publication history

      Accepted: January 17, 2023
      Received in revised form: January 15, 2023
      Received: May 24, 2021

      Publication stage

      In Press Journal Pre-Proof

      Footnotes

      Article Synopsis: Targeting the BMP-pSMAD pathway with anti-BMP2/4 inhibitors, effectively suppresses Barrett’s epithelium and promotes re-epithelialization by squamous cells in different preclinical mouse models. disease. In this study different mouse models were develop to study the efficacy of llama-derived anti-BMP2/4 antibodies. Anti-BMP2/4 antibodies shown to be an attractive molecular therapeutic option in the treatment of Barrett’s esophagus.

      Grant Support: This work was supported by the European Research Council (ERC) starting grant: ERC-StG 282079 TargetS4Barrett, ERC-POC 632258 BMP4EAC, and a Dutch government grant: LSH-TKI-PPP 2017. Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, Ministerio de Economía y Competitividad, Spain (Grant PI16/01642 & PI10/01096)

      Disclosures: The authors declare no conflict of interest

      Authors contribution: A.C.P.C, D.S, S.C. and K.K.K conceived and designed the experiments; A.C.P.C developed the in vivo ablation mouse model; D.S. developed the in vivo tamoxifen-inducible Noggin-/- mouse model; M.R, W.P and N.J.C developed the in vivo organoid mouse model; A.C.P.C, D.S., and M.R. performed the in vivo experiments and analysed the data; S.J.M.H. performed gene expression analysis; S.R-P. performed the in vitro experiments, SR-P and A.C.A-M analysed the in vitro data; A.C.P.C and D.S wrote the manuscript with the input from all the authors. S.C, K.K.K., W.P, K.W and N.J.C, reviewed and provided critical review; All authors have read and agreed to the published version of the manuscript.

      Identification

      DOI: https://doi.org/10.1016/j.jcmgh.2023.01.003

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      © 2023 The Authors. Published by Elsevier Inc. on behalf of the AGA Institute.

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