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

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

PROVIDER: PRJNA1266746 | ENA |

REPOSITORIES: ENA

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

Project description:Esophageal adenocarcinoma (EA) is increasingly common. EA is thought to arise from a precursor lesion, Barrett’s esophagus (BE), in which chronic bile and acid reflux from the stomach injures the esophagus and induces the esophageal squamous epithelium to transition to a mixed gastric and intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We established a biobank of human patient-derived BE organoids that recapitulated the molecular heterogeneity of BE. Bulk and single-cell transcriptomics, corroborated with analysis of patient tissues, pointed to BE differentiation depending on a balance between two transcription factors that govern foregut versus hindgut embryonic gastrointestinal development: SOX2 (driving esophageal and stomach differentiation) and CDX2 (driving intestinal differentiation). Using squamous-specific inducible Sox2 knockout (Krt5CreER/+; Sox2Δ/Δ;ROSA26LSLTdTomato/+) mice, we found increased basal proliferation and decreased differentiation in the foregut squamous epithelium. Remarkably, Sox2Δ/Δ mice also harbored expanded glands at the squamocolumnar junction, some of which lineage traced to Krt5-expressing cells, indicating metaplasia from squamous epithelium. 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 likely an initiating step in progression to BE and thence to EA.

2025-06-07 | PXD063992 | Pride

SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [CUT&Run]

Project description: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 (Krt5CreER/+; Sox2∆/∆; ROSA26tdTomato/+) 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.

2025-06-06 | GSE297942 | GEO

SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [scRNA-seq]

2025-06-06 | GSE298632 | GEO

SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [SOX2mousetissue]

Project description:SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [SOX2mousetissue]

| PRJNA1266595 | ENA

SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [scRNA-seq]

Project description:SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [scRNA-seq]

| PRJNA1270059 | ENA

SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [CUT&Run]

Project description:SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [CUT&Run]

| PRJNA1267002 | ENA

SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barretts esophagus development [humanBEorganoids]

Project description:SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barretts esophagus development [humanBEorganoids]

| PRJNA1266195 | ENA

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

Project description:Differentially expressed genes in SOX2 KO vs control forestomach organoids In this dataset, we include expression data from SOX2 KO forestomach organoid and control forestomach organoid

2025-06-06 | GSE297930 | GEO

SOX2 regulates foregut squamous epithelial homeostasis and is lost during Barrett’s esophagus development [SOX2mousetissue]

Project description:Differentially expressed genes in SOX2 KO vs control forestomachs In this dataset, we include expression data from 4 SOX2 KO forestomachs and 3 control forestomaches

2025-06-06 | GSE297858 | GEO

HOXA13 in etiology and oncogenic potential of Barrett’s esophagus [EPC2]

Project description: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 BE. 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.

2021-04-24 | GSE173169 | GEO

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