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Genetically-engineered mouse models of small cell lung cancer: the next generation

Oncogene volume 43, pages 457–469 (2024)Cite this article

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Abstract

Small cell lung cancer (SCLC) remains the most fatal form of lung cancer, with patients in dire need of new and effective therapeutic approaches. Modeling SCLC in an immunocompetent host is essential for understanding SCLC pathogenesis and ultimately discovering and testing new experimental therapeutic strategies. Human SCLC is characterized by near universal genetic loss of the RB1 and TP53 tumor suppressor genes. Twenty years ago, the first genetically-engineered mouse model (GEMM) of SCLC was generated using conditional deletion of both Rb1 and Trp53 in the lungs of adult mice. Since then, several other GEMMs of SCLC have been developed coupling genomic alterations found in human SCLC with Rb1 and Trp53 deletion. Here we summarize how GEMMs of SCLC have contributed significantly to our understanding of the disease in the past two decades. We also review recent advances in modeling SCLC in mice that allow investigators to bypass limitations of the previous generation of GEMMs while studying new genes of interest in SCLC. In particular, CRISPR/Cas9-mediated somatic gene editing can accelerate how new genes of interest are functionally interrogated in SCLC tumorigenesis. Notably, the development of allograft models and precancerous precursor models from SCLC GEMMs provides complementary approaches to GEMMs to study tumor cell-immune microenvironment interactions and test new therapeutic strategies to enhance response to immunotherapy. Ultimately, the new generation of SCLC models can accelerate research and help develop new therapeutic strategies for SCLC.

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Fig. 1: Frequently used SCLC GEMMs developed using classical mouse genetics.
Fig. 2: Approaches to make the “Next Generation” of SCLC GEMMs using CRISPR/Cas9 somatic engineering.
Fig. 3: Approaches to generate immunocompetent syngeneic mouse models of SCLC.

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Acknowledgements

We thank Julie Ko for the images of tumors. This work was supported by the NIH (MGO, R37CA269990; JS, CA231997; K-SP, U01CA224293; TGO, U24CA213274; DM, P50CA228944-01A1). JS is the Elaine and John Chambers Professor in Pediatric Cancer.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA

    Matthew G. Oser

  2. Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

    Matthew G. Oser

  3. Division of Human Biology, Fred Hutch Cancer Center, Seattle, WA, 98109, USA

    David MacPherson

  4. Department of Pharmacology & Cancer Biology, Duke University, Durham, NC, 27708, USA

    Trudy G. Oliver

  5. Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA

    Julien Sage

  6. Department of Genetics, Stanford University, Stanford, CA, 94305, USA

    Julien Sage

  7. Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22903, USA

    Kwon-Sik Park

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The authors wrote the manuscript and prepared the figures together.

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Correspondence to Matthew G. Oser or Kwon-Sik Park.

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Competing interests

MGO reports grants (current and past) from Eli Lilly, Takeda, Novartis, BMS, and Circle Pharma. JS has equity in, and is an advisor for, DISCO Pharmaceuticals. TGO has a patent related to SCLC subtyping and reports grants from Auron Therapeutics. The other authors declare no competing interests.

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Oser, M.G., MacPherson, D., Oliver, T.G. et al. Genetically-engineered mouse models of small cell lung cancer: the next generation. Oncogene 43, 457–469 (2024). https://doi.org/10.1038/s41388-023-02929-7

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  • DOI: https://doi.org/10.1038/s41388-023-02929-7

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