TY - JOUR
T1 - Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis
AU - Del Poggetto, Edoardo
AU - Ho, I. Lin
AU - Balestrieri, Chiara
AU - Yen, Er Yen
AU - Zhang, Shaojun
AU - Citron, Francesca
AU - Shah, Rutvi
AU - Corti, Denise
AU - Diaferia, Giuseppe R.
AU - Li, Chieh Yuan
AU - Loponte, Sara
AU - Carbone, Federica
AU - Hayakawa, Yoku
AU - Valenti, Giovanni
AU - Jiang, Shan
AU - Sapio, Luigi
AU - Jiang, Hong
AU - Dey, Prasenjit
AU - Gao, Sisi
AU - Deem, Angela K.
AU - Rose-John, Stefan
AU - Yao, Wantong
AU - Ying, Haoqiang
AU - Rhim, Andrew D.
AU - Genovese, Giannicola
AU - Heffernan, Timothy P.
AU - Maitra, Anirban
AU - Wang, Timothy C.
AU - Wang, Linghua
AU - Draetta, Giulio F.
AU - Carugo, Alessandro
AU - Natoli, Gioacchino
AU - Viale, Andrea
N1 - Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/9/17
Y1 - 2021/9/17
N2 - 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.
AB - 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.
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U2 - 10.1126/science.abj0486
DO - 10.1126/science.abj0486
M3 - Article
C2 - 34529467
AN - SCOPUS:85115126938
SN - 0036-8075
VL - 373
JO - Science
JF - Science
IS - 6561
M1 - eabj0486
ER -