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A gene–environment-induced epigenetic program initiates tumorigenesis

Author

Listed:
  • Direna Alonso-Curbelo

    (Memorial Sloan Kettering Cancer Center)

  • Yu-Jui Ho

    (Memorial Sloan Kettering Cancer Center)

  • Cassandra Burdziak

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medicine)

  • Jesper L. V. Maag

    (Memorial Sloan Kettering Cancer Center)

  • John P. Morris

    (Memorial Sloan Kettering Cancer Center)

  • Rohit Chandwani

    (Memorial Sloan Kettering Cancer Center
    Weill Cornell Medical College
    Weill Cornell Medical College)

  • Hsuan-An Chen

    (Memorial Sloan Kettering Cancer Center
    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
    Memorial Sloan Kettering Cancer Center)

  • John E. Wilkinson

    (University of Michigan School of Medicine)

  • Linas Mazutis

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Steven D. Leach

    (Memorial Sloan Kettering Cancer Center
    Dartmouth Norris Cotton Cancer Center
    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
    Howard Hughes Medical Institute)

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.

Suggested Citation

  • 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 & , 2021. "A gene–environment-induced epigenetic program initiates tumorigenesis," Nature, Nature, vol. 590(7847), pages 642-648, February.
  • Handle: RePEc:nat:nature:v:590:y:2021:i:7847:d:10.1038_s41586-020-03147-x
    DOI: 10.1038/s41586-020-03147-x
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    Citations

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    Cited by:

    1. Yuanyuan Chen & Reka Toth & Sara Chocarro & Dieter Weichenhan & Joschka Hey & Pavlo Lutsik & Stefan Sawall & Georgios T. Stathopoulos & Christoph Plass & Rocio Sotillo, 2022. "Club cells employ regeneration mechanisms during lung tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Yi Xu & Michael H. Nipper & Angel A. Dominguez & Zhenqing Ye & Naoki Akanuma & Kevin Lopez & Janice J. Deng & Destiny Arenas & Ava Sanchez & Francis E. Sharkey & Colin M. Court & Aatur D. Singhi & Hua, 2024. "Reconstitution of human PDAC using primary cells reveals oncogenic transcriptomic features at tumor onset," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Jong Ho Park & Mahsa Mortaja & Heehwa G. Son & Xutu Zhao & Lauren M. Sloat & Marjan Azin & Jun Wang & Michael R. Collier & Krishna S. Tummala & Anna Mandinova & Nabeel Bardeesy & Yevgeniy R. Semenov &, 2024. "Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Xiaowei Bian & Minna Piipponen & Zhuang Liu & Lihua Luo & Jennifer Geara & Yongjian Chen & Traimate Sangsuwan & Monica Maselli & Candice Diaz & Connor A. Bain & Evelien Eenjes & Maria Genander & Micha, 2024. "Epigenetic memory of radiotherapy in dermal fibroblasts impairs wound repair capacity in cancer survivors," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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