SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development

Ramon U. Jin; Yuanwei Xu; Tung-Shing Lih; Yang-Zhe Huang; Toni M. Nittolo; Blake E. Sells; Olivia M. Dres; Jean S. Wang; Qing Kay Li; Hui Zhang; Jason C. Mills

doi:10.1172/JCI190374

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Jin, R. in: PubMed | Google Scholar

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Xu, Y. in: PubMed | Google Scholar

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

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¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

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¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Nittolo, T. in: PubMed | Google Scholar

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Sells, B. in: PubMed | Google Scholar

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Dres, O. in: PubMed | Google Scholar

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Wang, J. in: PubMed | Google Scholar

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Li, Q. in: PubMed | Google Scholar

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Zhang, H. in: PubMed | Google Scholar

¹Division of Oncology, Washington University, Saint Louis, United States of America

²Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, United States of America

³Section of Gastroenterology, Baylor College of Medicine, Houston, United States of America

⁴Division of Gastroenterology, Washington University, Saint Louis, United States of America

Find articles by Mills, J. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI190374.
Copyright © 2025, Jin et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 30, 2025 - Version history

Esophageal adenocarcinoma (EA) is increasingly prevalent and is thought to arise from Barrett’s esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE’s molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2 knockout (Krt5^CreER/+; Sox2^∆/∆; ROSA26^tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at the squamocolumnar junction, some tracing back to Krt5-expressing cells. CUT&RUN analysis showed SOX2 bound and promoted differentiation-associated (e.g., Krt13) and repressed proliferation-associated (e.g., Mki67) targets. Thus, SOX2 is critical for foregut squamous epithelial differentiation and its decreased expression is likely an initiating step in progression to BE and thence to EA.

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development

Ramon U. Jin,¹ Yuanwei Xu,² Tung-Shing Lih,² Yang-Zhe Huang,³ Toni M. Nittolo,³ Blake E. Sells,¹ Olivia M. Dres,¹ Jean S. Wang,⁴ Qing Kay Li,² Hui Zhang,² and Jason C. Mills³

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SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development

Ramon U. Jin,1 Yuanwei Xu,2 Tung-Shing Lih,2 Yang-Zhe Huang,3 Toni M. Nittolo,3 Blake E. Sells,1 Olivia M. Dres,1 Jean S. Wang,4 Qing Kay Li,2 Hui Zhang,2 and Jason C. Mills3

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Ramon U. Jin,¹ Yuanwei Xu,² Tung-Shing Lih,² Yang-Zhe Huang,³ Toni M. Nittolo,³ Blake E. Sells,¹ Olivia M. Dres,¹ Jean S. Wang,⁴ Qing Kay Li,² Hui Zhang,² and Jason C. Mills³