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 Winkel, H. Scott Stadler, Tatiana Sandoval-Guzmán, Luc J. W. Laan, Ernst J. Kuipers, Ron Smits, Marco J. Bruno, Gwenny M. Fuhler, Nicholas J. Clemons and Maikel P. Peppelenbosch ()
Additional contact information
Vincent T. Janmaat: Erasmus MC - University Medical Center Rotterdam
Kateryna Nesteruk: Erasmus MC - University Medical Center Rotterdam
Manon C. W. Spaander: Erasmus MC - University Medical Center Rotterdam
Auke P. Verhaar: Erasmus MC - University Medical Center Rotterdam
Bingting Yu: Erasmus MC - University Medical Center Rotterdam
Rodrigo A. Silva: Erasmus MC - University Medical Center Rotterdam
Wayne A. Phillips: Division of Cancer Research, Peter MacCallum Cancer Centre
Marcin Magierowski: Erasmus MC - University Medical Center Rotterdam
Anouk Winkel: Erasmus MC - University Medical Center Rotterdam
H. Scott Stadler: Shriners Hospital for Children
Tatiana Sandoval-Guzmán: DFG-Center for Regenerative Therapies, Technische Universität Dresden
Luc J. W. Laan: Erasmus MC - University Medical Center Rotterdam
Ernst J. Kuipers: Erasmus MC - University Medical Center Rotterdam
Ron Smits: Erasmus MC - University Medical Center Rotterdam
Marco J. Bruno: Erasmus MC - University Medical Center Rotterdam
Gwenny M. Fuhler: Erasmus MC - University Medical Center Rotterdam
Nicholas J. Clemons: Division of Cancer Research, Peter MacCallum Cancer Centre
Maikel P. Peppelenbosch: Erasmus MC - University Medical Center Rotterdam

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23641-8

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