Lian Guodong, Malagola Ermanno, Wei Chengguo, Shi Qiongyu, Zhao Junfei, Hata Masahiro, Kobayashi Hiroki, Ochiai Yosuke, Zheng Biyun, Zhi Xiaofei, Wu Feijing, Tu Ruhong, Nápoles Osmel Companioni, Su Wenjing, Li Leping, Jing Changqing, Chen Man, Zamechek Leah, Friedman Richard, Nowicki-Osuch Karol, Quante Michael, Que Jianwen, Wang Timothy C
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Gut. 2025 Jan 17;74(2):182-196. doi: 10.1136/gutjnl-2024-332095.
While p53 mutations occur early in Barrett's oesophagus (BE) progression to oesophageal adenocarcinoma (EAC), their role in gastric cardia stem cells remains unclear.
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.
We used a BE mouse model (L2-IL1β) harbouring a 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.
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.
p53 mutation contributes to BE progression by increasing expansion and fitness of undifferentiated cardia progenitors and preventing their differentiation towards metaplasia.
虽然p53突变在巴雷特食管（BE）进展为食管腺癌（EAC）的早期就会出现，但其在贲门干细胞中的作用仍不清楚。
本研究调查p53突变对BE向EAC进展过程中贲门祖细胞的命运和功能的影响，特别是在慢性损伤的胁迫下。
我们使用携带p53突变（R172H）的BE小鼠模型（L2-IL1β）来研究p53对Cck2r贲门祖细胞的影响。我们采用谱系追踪、病理分析、类器官培养、单细胞RNA测序（scRNA-seq）和计算分析来研究祖细胞行为、分化模式和肿瘤进展的变化。此外，我们对分选的化生和突变祖细胞进行原位移植，以评估它们在体内的致瘤潜力。
p53突变起到一个开关的作用，可扩大祖细胞并抑制它们向化生的分化，但仅在慢性损伤的情况下。在L2-IL1β小鼠中，p53突变增加了祖细胞的扩增和谱系追踪，伴有从化生向发育异常的转变。scRNA-seq显示发育异常细胞直接来自突变祖细胞，而不是通过化生进展而来。在体外，p53突变提高了BE祖细胞的类器官形成效率、生长、DNA损伤抗性以及向非整倍体的进展。分选的化生细胞生长不佳，没有进展为发育异常，而突变祖细胞在原位移植中导致发育异常。计算分析表明，p53突变通过Notch激活抑制干细胞分化。
p53突变通过增加未分化贲门祖细胞的扩增和适应性并阻止它们向化生的分化，促进了BE的进展。
