A gene–environment-induced epigenetic program initiates tumorigenesis Journal Article


Authors: Alonso-Curbelo, D.; Ho, Y. J.; Burdziak, C.; Maag, J. L. V.; Morris, J. P. 4th; Chandwani, R.; Chen, H. A.; Tsanov, K. M.; Barriga, F. M.; Luan, W.; Tasdemir, N.; Livshits, G.; Azizi, E.; Chun, J.; Wilkinson, J. E.; Mazutis, L.; Leach, S. D.; Koche, R.; Pe’er, D.; Lowe, S. W.
Article Title: A gene–environment-induced epigenetic program initiates tumorigenesis
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 Kras oncogene 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 Kras mutation 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 Kras to 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. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Keywords: controlled study; human tissue; gene mutation; nonhuman; pancreas cancer; animal cell; mouse; animal tissue; gene expression; animal experiment; animal model; protein; cohort analysis; risk factor; carcinogenesis; epigenetics; chromatin; genomics; gene control; oncogene k ras; tumor; health risk; tissue injury; single cell analysis; genotype environment interaction; detection method; pancreas injury; interleukin 33; cancer; human; male; female; priority journal; article; pancreas tissue; induced response
Journal Title: Nature
Volume: 590
Issue: 7847
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2021-02-25
Start Page: 642
End Page: 648
Language: English
DOI: 10.1038/s41586-020-03147-x
PUBMED: 33536616
PROVIDER: scopus
PMCID: PMC8482641
DOI/URL:
Notes: Article -- Export Date: 1 April 2021 -- Source: Scopus
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MSK Authors
  1. Scott W Lowe
    249 Lowe
  2. Richard Patrick Koche
    173 Koche
  3. Steven Leach
    37 Leach
  4. Dana Pe'er
    110 Pe'er
  5. Linas Mazutis
    34 Mazutis
  6. Elham Azizi
    12 Azizi
  7. Jesper Lars Viktor Maag
    14 Maaaag
  8. Yu-jui Ho
    40 Ho
  9. Hsuan An Chen
    9 Chen
  10. Francisco M Barriga
    12 Barriga
  11. Jaeyoung Chun
    5 Chun
  12. Wei Luan
    10 Luan
  13. Kaloyan M Tsanov
    7 Tsanov