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TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice

Oncogene volume 41, pages 3423–3432 (2022)Cite this article

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A Correction to this article was published on 25 August 2022

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Abstract

Studies have shown that Nrf2E79Q/+ is one of the most common mutations found in human tumors. To elucidate how this genetic change contributes to lung cancer, we compared lung tumor development in a genetically-engineered mouse model (GEMM) with dual Trp53/p16 loss, the most common mutations found in human lung tumors, in the presence or absence of Nrf2E79Q/+. Trp53/p16-deficient mice developed combined-small cell lung cancer (C-SCLC), a mixture of pure-SCLC (P-SCLC) and large cell neuroendocrine carcinoma. Mice possessing the LSL-Nrf2E79Q mutation showed no difference in the incidence or latency of C-SCLC compared with Nrf2+/+ mice. However, these tumors did not express NRF2 despite Cre-induced recombination of the LSL-Nrf2E79Q allele. Trp53/p16-deficient mice also developed P-SCLC, where activation of the NRF2E79Q mutation associated with a higher incidence of this tumor type. All C-SCLCs and P-SCLCs were positive for NE-markers, NKX1-2 (a lung cancer marker) and negative for P63 (a squamous cell marker), while only P-SCLC expressed NRF2 by immunohistochemistry. Analysis of a consensus NRF2 pathway signature in human NE+-lung tumors showed variable activation of NRF2 signaling. Our study characterizes the first GEMM that develops C-SCLC, a poorly-studied human cancer and implicates a role for NRF2 activation in SCLC development.

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Fig. 1: Invasive tumors developed by Trp53fl/fl;p16fl/fl;Nrf2+/+ and Trp53fl/fl;p16fl/fl;Nrf2E79Q/+ mice.
Fig. 2: Characterization of P-SCLC developed by Trp53fl/fl;p16fl/fl;Nrf2E79Q/+ mice.
Fig. 3: Characterization and NRF2 genotyping of C-SCLC.
Fig. 4: Characterization of P-SCLC developed by Trp53fl/fl;p16fl/fl;Nrf2+/+ and Trp53fl/fl;p16fl/fl;Nrf2E79Q/+ mice.
Fig. 5: Heatmap of NRF2 target gene expression in human neuroendocrine lung tumors.
Fig. 6: Schematic representation of P-SCLC and C-SCLC development in Trp53fl/fl;p16fl/fl;Nrf2+/+ and Trp53fl/fl;p16fl/fl;Nrf2E79Q/+ GEMM.

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Code availability

The code used to generate the heatmap of target gene expression in human neuroendocrine lung tumors is available at https://github.com/jeremymsimon.

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Acknowledgements

The authors thank Charlene Santos and her staff at the UNC-LCCC Animal Studies Core for the breeding, monitoring, weighing, and isolation of tumors of the mice; Dawud Hilliard and his staff at the UNC-Lineberger Histopathology core 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.

Funding

This study was supported by a grant from the National Institutes of Environmental and Health Sciences (T32ES007126) (S.H.H), a Golberg Postdoctoral Fellow (S.H.H.), a grant from the National Cancer Institute (CA216051) (B.E.W, M.B.M.) and by grants 5R01CA244841-02, 5U01CA231844-04, and 5U24CA213274-05 (T.G.O.). These studies were also supported in part by a UNC Lineberger Clinical/Translational Research Award.

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Authors and Affiliations

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

    Samera H. Hamad, Stephanie A. Montgomery, Jeremy M. Simon, Brittany M. Bowman, M. Ben Major & Bernard E. Weissman

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

    Stephanie A. Montgomery & Bernard E. Weissman

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

    Jeremy M. Simon

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

    Jeremy M. Simon

  5. Department of Oncological Sciences, School of Medicine, University of Utah, Salt Lake City, UT, USA

    Kyle B. Spainhower & Trudy G. Oliver

  6. Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Ryan M. Murphy

  7. Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Erik S. Knudsen & Agnieszka K. Witkiewicz

  8. Division of National Toxicology Program, NIEHS/NIH, Research Triangle Park, NC, USA

    Suzanne E. Fenton

  9. Marsico Lung Institute, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    Scott H. Randell

  10. University of Tennessee Health Science Center for Cancer Research, Department of Medicine, Division of Hematology and Oncology, University of Tennessee, Memphis, TN, USA

    Jeremiah R. Holt & D. Neil Hayes

  11. Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA

    M. Ben Major

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Contributions

Conception: BEW and MBM; Experimental design, methodology, and implementation: SHH, SAM, BMB, KBS, RMM, ESK, SEF, SHR, AKW, TGO, BEW, and MBM; Analysis and interpretation of data (e.g., statistical analysis, bioinformatics): SHH, SAM, JMS, ESK, JRH, DNH, TGO, BEW, and MBM; Writing, review and/or revision of the manuscript: All authors; Study supervision: BEW and MBM.

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Correspondence to M. Ben Major or Bernard E. Weissman.

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This study was conducted after approval by Institutional Animal Care and Use Committee (IACUC) at the University of North Carolina at Chapel Hill (Protocol # 19-242.0)

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Hamad, S.H., Montgomery, S.A., Simon, J.M. et al. TP53, CDKN2A/P16, and NFE2L2/NRF2 regulate the incidence of pure- and combined-small cell lung cancer in mice. Oncogene 41, 3423–3432 (2022). https://doi.org/10.1038/s41388-022-02348-0

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