p53突变偏见smocamocomar enction祖细胞朝着发育不良而不是巴雷特食管中的变质
p53 mutation biases squamocolumnar junction progenitor cells towards dysplasia rather than metaplasia in Barrett's oesophagus
影响因子:25.80000
分区:医学1区 Top / 胃肠肝病学1区
发表日期:2025 Jan 17
作者:
Guodong Lian, Ermanno Malagola, Chengguo Wei, Qiongyu Shi, Junfei Zhao, Masahiro Hata, Hiroki Kobayashi, Yosuke Ochiai, Biyun Zheng, Xiaofei Zhi, Feijing Wu, Ruhong Tu, Osmel Companioni Nápoles, Wenjing Su, Leping Li, Changqing Jing, Man Chen, Leah Zamechek, Richard Friedman, Karol Nowicki-Osuch, Michael Quante, Jianwen Que, Timothy C Wang
摘要
虽然p53突变发生在巴雷特的食道（BE）向食管腺癌（EAC）的进展中，但它们在胃心脏病干细胞中的作用仍然不清楚。这项研究研究了p53突变对Cardia Orcenititor细胞的命运的影响，尤其是在EAC中进行的Cardia次病细胞的功能。突变（R172H）研究p53对CCK2R+ Cardia祖细胞的影响。我们采用了谱系追踪，病理分析，器官培养物，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，我们对分类的化生和突变体祖细胞进行了直接移植，以评估其在体内的肿瘤潜力。p53突变是扩展祖细胞并抑制其向化学分类的分化的转换，但仅在慢性造成慢性损伤中。在L2-IL1β小鼠中，p53突变增加了祖细胞的扩张和谱系追踪，从化学症转向发育不良。 SCRNA-SEQ揭示了非塑性细胞直接来自突变祖细胞，而不是通过化生型进展。在体外，p53突变增强了祖细胞的形成器官形成效率，生长，抗DNA损伤性和向非整倍性的发展。分类的化生细胞生长较差，没有发展为发育异常，而突变祖细胞在原位移植中导致发育不良。计算分析表明，p53突变通过Notch激活抑制了干细胞的分化。P53突变通过增加未分化的Cardia祖细胞的膨胀和适应性而导致进展，并防止其对化合物的分化。
Abstract
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 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.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.