2. Academic Validation
  3. Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer

Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer

  • Nat Cancer. 2025 Jul;6(7):1263-1282. doi: 10.1038/s43018-025-01003-3.
Laura Antonucci 1,  Na Li 2,  Angeles Duran 3,  Isidoro Cobo 4 5 6,  Chiara Nicoletti 7,  Kosuke Watari 1,  Shuvro Prokash Nandi 4 8,  Feng Zhu 9,  Yongmei Zhao 10,  Irene Riahi 11,  Motoyuki Tsuda 12,  Vidhi M Shah 12 13,  Terry Morgan 14,  Trent Waugh 13,  Luca Caputo 7,  Yuan Liu 1,  Alexandra Rundberg Nilsson 1,  Hongxu Xian 1,  Jelena Todoric 1 15,  Li Gu 1,  Elsa Sanchez-Lopez 16,  Guido Eibl 17,  Emily A Vucic 18,  Michal Krawczyk 19,  Qianlan Xu 19,  Andrew M Lowy 20,  Georgia Hatzivassiliou 21,  Merone Roose-Girma 21,  Dorota Skowronska-Krawczyk 19,  David A Scott 22,  Dafna Bar-Sagi 18,  Pablo Tamayo 23,  Ying Wu 10,  Rosalie C Sears 12 13 24,  Christopher K Glass 4,  Ludmil B Alexandrov 4 8 25,  Pier Lorenzo Puri 7,  David W Dawson 11,  Yinling Hu 9,  Maria T Diaz-Meco 3,  Jorge Moscat 3,  Michael Karin 26
Affiliations

Affiliations

  • 1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • 2 Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Jinan, China.
  • 3 Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • 4 Department of Cellular & Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • 5 Division of Clinical Immunology & Rheumatology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 6 Comprehensive Arthritis, Musculoskeletal, Bone and Autoimmunity Center, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 7 Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 8 Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • 9 Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 10 CCR Sequencing Facility Bioinformatics Group, Bioinformatics and Computational Science Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 11 Departments of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
  • 12 Department of Molecular and Medical Genetics, School of Medicine Oregon Health and Science University, Portland, OR, USA.
  • 13 Brenden-Colson Center for Pancreatic Care, School of Medicine Oregon Health and Science University, Portland, OR, USA.
  • 14 Department of Pathology, School of Medicine Oregon Health and Science University, Portland, OR, USA.
  • 15 Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
  • 16 Department of Orthopedic Surgery, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • 17 Department of Surgery, University of California, Los Angeles, Los Angeles, CA, USA.
  • 18 Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
  • 19 Department of Physiology and Biophysics, Center for Translational Vision Research, School of Medicine, University of California, Irvine, Irvine, CA, USA.
  • 20 Department of Surgery, Division of Surgical Oncology, Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • 21 Genentech, Inc., San Francisco, CA, USA.
  • 22 Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
  • 23 Center for Novel Therapeutics and Division of Medical Genetics, Department of Medicine, Moores Cancer Center, University of California, San Diego School of Medicine, La Jolla, CA, USA.
  • 24 Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • 25 Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
  • 26 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California, San Diego School of Medicine, La Jolla, CA, USA. karinoffice@health.ucsd.edu.
PMID: 40588523 DOI: 10.1038/s43018-025-01003-3
Abstract

Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant H2O2 induced Organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the Histone Methyltransferase EZH2. Congruently, nonoxidizing NRF2 activators triggered Organoid malignant conversion through NRF2 and EZH2, establishing a hitherto unknown epigenetic mechanism underlying PanIN-to-PDAC progression. While NRF2 induced EZH2 gene transcription in mouse and human PDAC, EZH2, a general repressor, coactivated transcription of NRF2-encoding NFE2L2 and interacted with Other transcription factors to induce genes that sustain PDAC metabolic demands. The self-amplifying NRF2-EZH2 epigenetic loop also accounted for inflammation-driven PanIN-to-PDAC progression in vivo and was upregulated in established human PDAC, whose malignancy was maintained by NRF2 binding to the EZH2 promoter.

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