Epithelial memory of inflammation limits tissue damage while promoting pancreatic tumorigenesis.
Acinar Cells
/ pathology
Animals
Carcinogenesis
Carcinoma, Pancreatic Ductal
/ genetics
Cell Transformation, Neoplastic
Cells, Cultured
Cellular Reprogramming
Chromatin
/ metabolism
Early Growth Response Protein 1
/ genetics
Enzyme Precursors
/ metabolism
Epigenesis, Genetic
Epithelial Cells
/ pathology
Female
Genes, ras
MAP Kinase Signaling System
Male
Metaplasia
Mice
Mutation
Pancreas
/ metabolism
Pancreatitis
/ genetics
Spheroids, Cellular
Transcriptome
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
17 Sep 2021
17 Sep 2021
Historique:
entrez:
16
9
2021
pubmed:
17
9
2021
medline:
25
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34529467
doi: 10.1126/science.abj0486
pmc: PMC9733946
mid: NIHMS1850331
doi:
Substances chimiques
Chromatin
0
Early Growth Response Protein 1
0
Egr1 protein, mouse
0
Enzyme Precursors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
eabj0486Subventions
Organisme : NCI NIH HHS
ID : P50 CA221707
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA117969
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258917
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA218891
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA262822
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA218891
Pays : United States
Commentaires et corrections
Type : CommentIn
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