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Activating NRF2E79Q mutation alters the differentiation of human non-small cell lung cancer

Cancer Gene Therapy volume 32, pages 1428–1438 (2025)Cite this article

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Abstract

The NRF2 signaling pathway promotes tumor initiation, progression and resistance to chemotherapy, radiation therapy and immune checkpoint inhibitors. The mechanisms underlying the biology of NRF2-active tumors are varied and include altered cellular metabolism, a reductive shift in redox state, and immunosuppression. Here we determined the molecular and phenotypic impact of NRF2 activation on two human non-small cell lung cancer (NSCLC) cell models. Inducible expression of NRF2E79Q, a common activating NRF2 mutation, in H358 lung adenocarcinoma (LUAD) cells altered cellular morphology and increased xenograft tumor growth in mice but not in 2D cell culture. In contrast, NRF2E79Q expression in H596 lung adeno-squamous cell carcinoma altered cellular morphology, increased neuroendocrine marker gene expression, but did not impact tumor growth in 2D or in xenografts. Gene expression profiling revealed shared and unique NRF2 transcriptional programs between these models, some of which were shared in primary lung tumors. Collectively, our findings reveal context-dependent effects of NRF2 activation on the growth and differentiation state of two human NSCLC models, supporting a role for NRF2 activation in altering the differentiation of human NSCLC during tumor progression.

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Fig. 1: Changes in differentiation of human NSCLC cell lines after NRF2E79Q induction in vitro.
Fig. 2: Tumor growth of human NSCLC cell lines in vitro and in vivo ± NRF2E79Q induction.
Fig. 3: In vivo induction of NRF2E79Q in human lung adenocarcinoma (H358 pIND20 NRF2E79Q-MP) cell line.
Fig. 4: In vivo induction of NRF2E79Q in human adeno-squamous cell carcinoma (H596 pIND20 NRF2E79Q-MP) cell line.
Fig. 5: Enrichment score of MYC pathway signature in primary human tumors and human NSCLC cell lines used in this study.
Fig. 6: Enrichment score of YAP1 signaling pathway in primary human tumors and human NSCLC cell lines used in this study.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and its Supplementary Figures and Tables. The RNA-seq data have been deposited in the NCBI GEO database (GSE289043). Raw data that support the findings of this study are available from the corresponding author (SHH), upon reasonable request.

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Acknowledgements

The authors thank Charlene Santos and her staff at the UNC-LCCC Animal Studies Core for the monitoring, weighing, and isolation of tumors of the mice; Dawud Hilliard, Gabriela Cruz, and the staff at the UNC-LCCC Pathology Services Core Facility for tissue processing and staining for H&E and IHC, and Dr. Pablo Ariel and his staff at the UNC Microscopy Services Laboratory for their help with the microscopy studies. This study was supported by a grant from the National Institutes of Environmental and Health Sciences (T32ES007126) SHH, a Goldberg Postdoctoral Fellow (SHH), and a grant from the National Cancer Institute (CA216051) (BEW and MBM). These studies were also supported in part by the Surgery Department at Cooper University Health Care, Cooper Medical School of Rowan University, and MD Anderson Cancer Center at Cooper.

Author information

Author notes

  1. Jeremy M. Simon

    Present address: Department of Data Science, Dana-Farber Cancer Institute, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA

  2. These authors contributed equally: Hansa Joshi, T. Hess.

Authors and Affiliations

  1. Surgery Department, Cooper Medical School of Rowan University, Camden, NJ, USA

    Samera H. Hamad, Gord Zhu, Francis R. Spitz & David Shersher

  2. Surgery Department, Cooper University Health Care, Camden, NJ, USA

    Samera H. Hamad, Hansa Joshi, T. Hess, Zena Saleh, Gord Zhu, Francis R. Spitz & David Shersher

  3. MD Anderson Cancer Center at Cooper, Camden, NJ, USA

    Samera H. Hamad, Francis R. Spitz & David Shersher

  4. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Samera H. Hamad, Stuart R. Jefferys, Rani S. Sellers, Travis Shrank, Rayvon T. Moore, David Corcoran, Jeremy M. Simon, Michael B. Major & Bernard E. Weissman

  5. Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Samera H. Hamad & Bernard E. Weissman

  6. College of Science and Mathematics, Rowan University, Glassboro, NJ, USA

    Nasrine Bendjilali

  7. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Rani S. Sellers & Bernard E. Weissman

  8. Department of Otolaryngology-Head and Neck Surgery, The University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, USA

    Travis Shrank

  9. Department of Genetics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    David Corcoran & Jeremy M. Simon

  10. UNC Neuroscience Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    David Corcoran & Jeremy M. Simon

  11. Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, USA

    Michael B. Major

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Contributions

SHH: Conception, study supervision, experimental design, methodology, data analysis, interpretation of data, and writing, review, and revision of the manuscript; HJ: Conducting experiments, and help in writing, review and revision of the manuscript; TH: Conducting experiments, and help in writing, review and revision of the manuscript; SRJ: Data analysis, bioinformatics, and help in writing, review and revision of the manuscript; ZS: Conducting experiments, and help in review and revision of the manuscript; NB: Statistical analysis, and help in writing, review and revision of the manuscript; RS: Methodology, data analysis and interpretation, and help in review and revision of the manuscript; GZ: Analysis and interpretation of data, and help in review and revision of the manuscript; TS: Interpretation of data, and help in review and revision of the manuscript; RTM: Conducting experiments, and help in review and revision of the manuscript; DC: Bioinformatics, and help in review and revision of the manuscript; JMS: Bioinformatics, and help in review and revision of the manuscript; FRS: Study supervision, interpretation of data, and help in review and revision of the manuscript; DS: Study supervision, interpretation of data, and help in review and revision of the manuscript; MBM: Study supervision, interpretation of data, and help in writing, review, and revision of the manuscript; BEW: Conception, study supervision, experimental design, methodology, data analysis, interpretation of data, and help in writing, review, and revision of the manuscript.

Corresponding author

Correspondence to Samera H. Hamad.

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Animal studies were conducted following an approved protocol (#19-242.0) established by Institutional Animal Care and Use Committee (IACUC) at the University of North Carolina at Chapel Hill, in accordance with the guidelines of the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals.

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Hamad, S.H., Joshi, H., Hess, T. et al. Activating NRF2E79Q mutation alters the differentiation of human non-small cell lung cancer. Cancer Gene Ther 32, 1428–1438 (2025). https://doi.org/10.1038/s41417-025-00966-w

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