CDKN2A-p16 deletion and activated KRAS drive Barrett's-like gland hyperplasia-metaplasia and synergize in the development of dysplasia pre-cancer lesions

Authors

Jing Sun, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
Jorge L. Sepulveda, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
Elena V. Komissarova, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
Caitlin Hills, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
Tyler D. Seckar, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
Narine M. LeFevre, Department of Pharmacology & Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC.
Hayk Simonyan, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.
Colin Young, Department of Pharmacology & Physiology, George Washington University, School of Medicine and Health Sciences, Washington, DC.
Gloria Su, Department of Pathology and Cell Biology, Columbia University, New York, NY.
Armando Del Portillo, Department of Pathology and Cell Biology, Columbia University, New York, NY.
Timothy C. Wang, Division of Digestive and Liver diseases, Department of Medicine, Columbia University, New York, NY.
Antonia R. Sepulveda, Department of Pathology, George Washington University School of Medicine and Health Sciences, Washington, DC.

Document Type

Journal Article

Publication Date

1-29-2024

Journal

Cellular and molecular gastroenterology and hepatology

DOI

10.1016/j.jcmgh.2024.01.014

Abstract

BACKGROUND & AIMS: Barrett's esophagus (BE) is the precursor of esophageal dysplasia and adenocarcinoma (EAC). CDKN2A-p16 deletions were reported in 34-74% of BE patients who progressed to dysplasia and EAC, suggesting that p16 loss may drive neoplastic progression. KRAS activation frequently occurs in EAC and pre-cancer lesions. LGR5+ stem cells in the squamocolumnar-junction (SCJ) of mouse stomach, contribute as BE progenitors. We aimed to determine the functional effects of p16 loss and KRAS activation in Barrett's-like metaplasia and dysplasia development. METHODS: We established mouse models with conditional knockout of CDKN2A-p16 (p16KO) and/or activated KRAS expression in interleukin-1b transgenic mice targeting SCJ LGR5+ cells and characterized histologic alterations (mucous-gland hyperplasia/metaplasia, inflammation, and dysplasia) in mouse SCJ. Gene expression was determined by microarray, RNAseq, and immunohistochemistry of SCJ tissues and cultured 3D organoids. RESULTS: p16KO mice exhibited increased mucous-gland hyperplasia/metaplasia vs. controls (p=.0051). Combined p16KO+KRAS resulted in more frequent dysplasia and higher dysplasia scores with 82% of p16KO+KRAS mice developing high-grade dysplasia (p=0.0036). SCJ transcriptome analysis showed several activated pathways in p16KO vs. control mice (apoptosis, TNF-alpha/NFkB, proteasome degradation, p53 signaling, MAPK, KRAS, and G1-to-S transition). CONCLUSIONS: p16 deletion in LGR5+ cell precursors triggers increased SCJ mucous-gland hyperplasia/metaplasia. KRAS synergizes with p16 deletion resulting in higher grades of SCJ glandular dysplasia, mimicking Barrett's high-grade dysplasia. These genetically modified mouse models establish a functional role of p16 and activated KRAS in the progression of Barrett's like lesions to dysplasia in mice, representing an in vivo model of esophageal pre-cancer. Derived 3D organoid models further provide in vitro modeling opportunities of esophageal pre-cancer stages.

APA Citation

Sun, Jing; Sepulveda, Jorge L.; Komissarova, Elena V.; Hills, Caitlin; Seckar, Tyler D.; LeFevre, Narine M.; Simonyan, Hayk; Young, Colin; Su, Gloria; Del Portillo, Armando; Wang, Timothy C.; and Sepulveda, Antonia R., "CDKN2A-p16 deletion and activated KRAS drive Barrett's-like gland hyperplasia-metaplasia and synergize in the development of dysplasia pre-cancer lesions" (2024). GW Authored Works. Paper 4109.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4109

Department

Pathology