Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer PMID: 40588523

ADC Targets in Oncology

2026-04-10

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

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. [email protected].

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.