A gene–environment-induced epigenetic program initiates tumorigenesis

Direna Alonso-Curbelo, Yu-Jui Ho, Cassandra Burdziak, Jesper L. V. Maag, John P. Morris, Rohit Chandwani, Hsuan-An Chen, Kaloyan M. Tsanov, Francisco M. Barriga, Wei Luan, Nilgun Tasdemir, Geulah Livshits, Elham Azizi, Jaeyoung Chun, John E. Wilkinson, Linas Mazutis, Steven D. Leach, Richard Koche, Dana Pe’er and Scott W. Lowe ()
Additional contact information
Direna Alonso-Curbelo: Memorial Sloan Kettering Cancer Center
Yu-Jui Ho: Memorial Sloan Kettering Cancer Center
Cassandra Burdziak: Memorial Sloan Kettering Cancer Center
Jesper L. V. Maag: Memorial Sloan Kettering Cancer Center
John P. Morris: Memorial Sloan Kettering Cancer Center
Rohit Chandwani: Memorial Sloan Kettering Cancer Center
Hsuan-An Chen: Memorial Sloan Kettering Cancer Center
Kaloyan M. Tsanov: Memorial Sloan Kettering Cancer Center
Francisco M. Barriga: Memorial Sloan Kettering Cancer Center
Wei Luan: Memorial Sloan Kettering Cancer Center
Nilgun Tasdemir: Memorial Sloan Kettering Cancer Center
Geulah Livshits: Memorial Sloan Kettering Cancer Center
Elham Azizi: Memorial Sloan Kettering Cancer Center
Jaeyoung Chun: Memorial Sloan Kettering Cancer Center
John E. Wilkinson: University of Michigan School of Medicine
Linas Mazutis: Memorial Sloan Kettering Cancer Center
Steven D. Leach: Memorial Sloan Kettering Cancer Center
Richard Koche: Memorial Sloan Kettering Cancer Center
Dana Pe’er: Memorial Sloan Kettering Cancer Center
Scott W. Lowe: Memorial Sloan Kettering Cancer Center

Nature, 2021, vol. 590, issue 7847, 642-648

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-020-03147-x

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