Salvador-Barbero Beatriz, Alatsatianos Markella, Morton Jennifer P, Sansom Owen J, Hogan Catherine
European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom.
Cancer Research UK Scotland Institute, Glasgow, United Kingdom; School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
Gastroenterology. 2025 Apr 7. doi: 10.1053/j.gastro.2025.02.042.
BACKGROUND & AIMS: The adult pancreas protects against cancer by actively expelling genetically mutated cells. Pancreatic cancer starts with cells carrying KRAS mutations; however, it is not clear how some KRAS mutant cells override cell elimination mechanisms to survive in tissues.
An in vivo mouse model of sporadic tumorigenesis was used to induce Kras and/or Tp53 mutations in low numbers of cells in the adult pancreas. The mutant cell fate was monitored over time using quantitative fluorescence imaging. Gene signatures of noneliminated mutant cell populations were identified using bulk RNA sequencing. Differential gene expression was overlapped with publicly available datasets. Key molecular pathways were validated in murine pancreas using immunofluorescence and functionally tested using inhibitor studies in vivo and epithelial coculture systems in vitro.
Although most genetically mutant cells are eliminated from the adult pancreas, a population of KRASG12D- or p53R172H-expressing cells are stably retained. Wnt5a signaling, cell dormancy, and stemness were identified as key features of surviving KrasG12D cells in vivo. Wnt5a specifically inhibits apical extrusion of RasV12 cells by promoting stable E-cadherin-based cell-cell adhesions at RasV12: normal cell-cell boundaries in vitro. In the pancreas, Wnt signaling, E-cadherin, and β-catenin are increased at cell-cell contacts between noneliminated KrasG12D cells and normal neighbors. Active Wnt signaling is a general mechanism required to promote KrasG12D and p53R172H cell retention and cell survival in vivo.
RAS mutant cells activate Wnt5a and cell dormancy to avoid cell expulsion and to survive in the adult pancreas.
成年胰腺通过主动排出基因变异细胞来预防癌症。胰腺癌始于携带KRAS突变的细胞；然而，尚不清楚一些KRAS突变细胞如何克服细胞清除机制而在组织中存活。
使用散发性肿瘤发生的体内小鼠模型，在成年胰腺的少量细胞中诱导Kras和/或Tp53突变。使用定量荧光成像随时间监测突变细胞的命运。使用批量RNA测序鉴定未被清除的突变细胞群体的基因特征。将差异基因表达与公开可用的数据集进行比对。在小鼠胰腺中使用免疫荧光验证关键分子途径，并在体内使用抑制剂研究和体外上皮共培养系统进行功能测试。
尽管大多数基因变异细胞从成年胰腺中被清除，但仍有一群表达KRASG12D或p53R172H的细胞被稳定保留。Wnt5a信号传导、细胞休眠和干性被确定为体内存活的KrasG12D细胞的关键特征。Wnt5a通过在体外RasV12：正常细胞-细胞边界处促进基于E-钙粘蛋白的稳定细胞-细胞粘附，特异性抑制RasV12细胞的顶端挤出。在胰腺中，未被清除的KrasG12D细胞与正常邻居之间的细胞-细胞接触处，Wnt信号传导、E-钙粘蛋白和β-连环蛋白增加。活跃的Wnt信号传导是促进体内KrasG12D和p53R172H细胞保留和细胞存活所需的一般机制。
RAS突变细胞激活Wnt5a和细胞休眠以避免细胞排出并在成年胰腺中存活。
