Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis

Edoardo Del Poggetto, I. Lin Ho, Chiara Balestrieri, Er Yen Yen, Shaojun Zhang, Francesca Citron, Rutvi Shah, Denise Corti, Giuseppe R. Diaferia, Chieh Yuan Li, Sara Loponte, Federica Carbone, Yoku Hayakawa, Giovanni Valenti, Shan Jiang, Luigi Sapio, Hong Jiang, Prasenjit Dey, Sisi Gao, Angela K. DeemStefan Rose-John, Wantong Yao, Haoqiang Ying, Andrew D. Rhim, Giannicola Genovese, Timothy P. Heffernan, Anirban Maitra, Timothy C. Wang, Linghua Wang, Giulio F. Draetta, Alessandro Carugo, Gioacchino Natoli, Andrea Viale

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, KRAS mutations accelerate tumor development in mouse models. We report that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, pancreatic epithelial cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thereby limiting tissue damage through a rapid decrease of zymogen production. We propose that because activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis.

Original languageEnglish (US)
Article numbereabj0486
JournalScience
Volume373
Issue number6561
DOIs
StatePublished - Sep 17 2021

ASJC Scopus subject areas

  • General

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core

Fingerprint

Dive into the research topics of 'Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis'. Together they form a unique fingerprint.

Cite this