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

祖细胞 生物 癌症研究 化生 发育不良 祖细胞 干细胞 病理 移植 突变 细胞分化 免疫学 细胞生物学 遗传学 医学 内科学 基因
作者
Guodong Lian,Ermanno Malagola,Chengguo Wei,Qiongyu Shi,Junfei Zhao,Masahiro Hata,Hiroki Kobayashi,Y. Ochiai,Biyun Zheng,Xiaofei Zhi,Feijing Wu,Ru‐Hong Tu,Osmel Companioni,Wenjing Su,Leping Li,Changqing Jing,Man Chen,Leah Zamechek,Richard A. Friedman,Karol Nowicki-Osuch,Michael Quante,Jianwen Que,Timothy C Wang
出处
期刊:Gut [BMJ]
卷期号:: gutjnl-332095
标识
DOI:10.1136/gutjnl-2024-332095
摘要

Background While p53 mutations occur early in Barrett’s oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear. Objective This 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. Design We 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. Results The 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. Conclusions p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.
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