TY - JOUR
T1 - Inhibition of BMP2 and BMP4 Represses Barrett's Esophagus While Enhancing the Regeneration of Squamous Epithelium in Preclinical Models
AU - Correia, Ana C. P.
AU - Straub, Danielle
AU - Read, Matthew
AU - Hoefnagel, Sanne J. M.
AU - Romero-Pinedo, Salvador
AU - Abadía-Molina, Ana C.
AU - Clemons, Nicholas J.
AU - Wang, Kenneth
AU - Calpe, Silvia
AU - Phillips, Wayne
AU - Krishnadath, Kausilia K.
N1 - Funding Information: Funding 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). Funding Information: Funding 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). Publisher Copyright: © 2023 The Authors
PY - 2023/1/1
Y1 - 2023/1/1
N2 - Background & Aims: Barrett's esophagus is considered to be a metaplastic lesion that predisposes for esophageal adenocarcinoma. Development of Barrett's esophagus is considered to be driven by sonic hedgehog mediated bone morphogenetic protein (BMP) signaling. We aimed to investigate in preclinical in vivo models whether 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 squamocolumnar 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 attenuate 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.
AB - Background & Aims: Barrett's esophagus is considered to be a metaplastic lesion that predisposes for esophageal adenocarcinoma. Development of Barrett's esophagus is considered to be driven by sonic hedgehog mediated bone morphogenetic protein (BMP) signaling. We aimed to investigate in preclinical in vivo models whether 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 squamocolumnar 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 attenuate 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.
KW - BMP2
KW - BMP4
KW - Barrett's Esophagus
KW - Llama-Derived Single-Domain Antibody
KW - Preclinical Models
KW - Targeted Therapy
UR - http://www.scopus.com/inward/record.url?scp=85150852056&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jcmgh.2023.01.003
DO - https://doi.org/10.1016/j.jcmgh.2023.01.003
M3 - Article
C2 - 36706916
SN - 2352-345X
VL - 15
SP - 1199
EP - 1217
JO - Cellular and Molecular Gastroenterology and Hepatology
JF - Cellular and Molecular Gastroenterology and Hepatology
IS - 5
ER -