Journal Article

p53 mutation biases squamocolumnar junction progenitor cells towards dysplasia rather than metaplasia in Barrett’s oesophagus

Friedman, Richard, Zamechek, Leah, Ochiai, Yosuke, Malagola, Ermanno, Jing, Changqing, Wang, Timothy C, Lian, Guodong, Wu, Feijing, Quante, Michael, Hata, Masahiro, Wei, Chengguo, Chen, Man, Tu, Ruhong, Li, Leping, Su, Wenjing, Zhao, Junfei, Nápoles, Osmel Companioni, Nowicki-Osuch, Karol, Shi, Qiongyu, Kobayashi, Hiroki, Zhi, Xiaofei, Que, Jianwen, Zheng, Biyun

2025

Overview

BackgroundWhile p53 mutations occur early in Barrett’s oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear.ObjectiveThis study investigates the impact of p53 mutation on the fate and function of cardia progenitor cells in BE to EAC progression, particularly under the duress of chronic injury.DesignWe used a BE mouse model (L2-IL1β) harbouring a Trp53 mutation (R172H) to study the effects of p53 on Cck2r+ cardia progenitor cells. We employed lineage tracing, pathological analysis, organoid cultures, single-cell RNA sequencing (scRNA-seq) and computational analyses to investigate changes in progenitor cell behaviour, differentiation patterns and tumour progression. Additionally, we performed orthotopic transplantation of sorted metaplastic and mutant progenitor cells to assess their tumourigenic potential in vivo.ResultsThe p53 mutation acts as a switch to expand progenitor cells and inhibit their differentiation towards metaplasia, but only amidst chronic injury. In L2-IL1β mice, p53 mutation increased progenitors expansion and lineage-tracing with a shift from metaplasia to dysplasia. scRNA-seq revealed dysplastic cells arise directly from mutant progenitors rather than progressing through metaplasia. In vitro, p53 mutation enhanced BE progenitors’ organoid-forming efficiency, growth, DNA damage resistance and progression to aneuploidy. Sorted metaplastic cells grew poorly with no progression to dysplasia, while mutant progenitors gave rise to dysplasia in orthotopic transplantation. Computational analyses indicated that p53 mutation inhibited stem cell differentiation through Notch activation.Conclusionsp53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - pathology / Aneuploidy / Animals / Barrett Esophagus - genetics / Barrett Esophagus - pathology / BARRETT'S METAPLASIA / BARRETT'S OESOPHAGUS / Cardia - pathology / Cell activation / Cell Differentiation / Cloning / Computer applications / Disease Models, Animal / Disease Progression / DNA damage / DYSPLASIA / Esophageal cancer / Esophageal Neoplasms - genetics / Esophageal Neoplasms - pathology / Esophagus / Histopathology / Inflammation / Medical prognosis / Metaplasia / Metaplasia - genetics / Mice / Mutants / Mutation / OESOPHAGEAL CANCER / Oesophagus / Organoids / Progenitor cells / STEM CELLS / Stem Cells - pathology / Transplantation / Tumor Suppressor Protein p53 - genetics / Tumors