Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

KRASG12D cells override homeostatic cell elimination mechanisms in adult pancreas via Wnt5a and cell dormancy

Salvador-Barbero, Beatriz, Alatsatianos, Markella, Morton, Jennifer P., Sansom, Owen J. and Hogan, Catherine ORCID: https://orcid.org/0000-0002-1012-0896 2025. KRASG12D cells override homeostatic cell elimination mechanisms in adult pancreas via Wnt5a and cell dormancy. Gastroenterology 10.1053/j.gastro.2025.02.042

[thumbnail of PIIS0016508525006031 (1).pdf]
Preview
PDF - Accepted Post-Print Version
Available under License Creative Commons Attribution.

Download (16MB) | Preview

Abstract

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. Methods: 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. Results: 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. Conclusions: RAS mutant cells activate Wnt5a and cell dormancy to avoid cell expulsion and to survive in the adult pancreas.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Schools > Biosciences
Publisher: Elsevier
ISSN: 0016-5085
Date of First Compliant Deposit: 24 February 2025
Date of Acceptance: 23 February 2025
Last Modified: 21 May 2025 09:08
URI: https://orca.cardiff.ac.uk/id/eprint/176411

Actions (repository staff only)

Edit Item Edit Item

Downloads

Downloads per month over past year

View more statistics