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A gene–environment-induced epigenetic program initiates tumorigenesis

Authors :
Alonso-Curbelo, Direna
Ho, Yu-Jui
Burdziak, Cassandra
Maag, Jesper L. V.
Morris, John P.
Chandwani, Rohit
Chen, Hsuan-An
Tsanov, Kaloyan M.
Barriga, Francisco M.
Luan, Wei
Tasdemir, Nilgun
Livshits, Geulah
Azizi, Elham
Chun, Jaeyoung
Wilkinson, John E.
Mazutis, Linas
Leach, Steven D.
Koche, Richard
Pe’er, Dana
Lowe, Scott W.
Source :
Nature; February 2021, Vol. 590 Issue: 7847 p642-648, 7p
Publication Year :
2021

Abstract

Tissue damage increases the risk of cancer through poorly understood mechanisms1. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Krasoncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Krasmutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an ‘acinar-to-neoplasia’ chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Krasto unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene–environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.

Details

Language :
English
ISSN :
00280836 and 14764687
Volume :
590
Issue :
7847
Database :
Supplemental Index
Journal :
Nature
Publication Type :
Periodical
Accession number :
ejs55264858
Full Text :
https://doi.org/10.1038/s41586-020-03147-x