HOXA13 in etiology and oncogenic potential of Barrett’s esophagus

Vincent T. Janmaat, Kateryna Nesteruk, Manon C.W. Spaander, Auke P. Verhaar, Bingting Yu, Rodrigo A. Silva, Wayne A. Phillips, Marcin Magierowski, Anouk van de Winkel, H. Scott Stadler, Tatiana Sandoval-Guzmán, Luc J.W. van der Laan, Ernst J. Kuipers, Ron Smits, Marco J. Bruno, Gwenny M. Fuhler, Nicholas J. Clemons, Maikel P. Peppelenbosch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

Barrett’s esophagus in gastrointestinal reflux patients constitutes a columnar epithelium with distal characteristics, prone to progress to esophageal adenocarcinoma. HOX genes are known mediators of position-dependent morphology. Here we show HOX collinearity in the adult gut while Barrett’s esophagus shows high HOXA13 expression in stem cells and their progeny. HOXA13 overexpression appears sufficient to explain both the phenotype (through downregulation of the epidermal differentiation complex) and the oncogenic potential of Barrett’s esophagus. Intriguingly, employing a mouse model that contains a reporter coupled to the HOXA13 promotor we identify single HOXA13-positive cells distally from the physiological esophagus, which is mirrored in human physiology, but increased in Barrett’s esophagus. Additionally, we observe that HOXA13 expression confers a competitive advantage to cells. We thus propose that Barrett’s esophagus and associated esophageal adenocarcinoma is the consequence of expansion of this gastro-esophageal HOXA13-expressing compartment following epithelial injury.

Original languageEnglish
Article number3354
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 7 Jun 2021

Bibliographical note

Funding Information:
We would like to acknowledge H.F.B.M. Sleddens, H. Stoop, M.H.W. van Dullemen, P. Vasic, I.T.A. Edelijn, M.J. van der Lee, P.J. Zwalua, W.W. van Dam, E. Zielhuis, J. Knoop, M. Doukas, A.L. Nigg and T.P.P. van den Bosch, Erasmus MC - University Medical Center Rotterdam, for their involvement in investigation, W.N.M. Dinjens for providing material, and F. McKeon, The Jackson Laboratory for Genomic Medicine, for conceptualization and providing resources. FAPESP n. 2016/01139-0; 2017/01046-5 for funding. M.Magierowski was supported by a grant from National Science Centre (Poland): UMO-2016/23/D/NZ4/01913.

Publisher Copyright:
© 2021, The Author(s).

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