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Genetically-engineered mouse models of small cell lung cancer: the next generation
Matthew G Oser1,2, David MacPherson3, Trudy G Oliver4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA. matthew_oser@dfci.harvard.edu.
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.
Insights
New mouse models accelerate research for small cell lung cancer (SCLC), a fatal disease. These models aid in understanding SCLC and developing effective new therapies.
Area of Science:
- Oncology
- Genetics
- Immunology
Background:
- Small cell lung cancer (SCLC) is a highly fatal lung cancer subtype with limited therapeutic options.
- Genetic inactivation of RB1 and TP53 tumor suppressor genes is a hallmark of human SCLC.
- Genetically-engineered mouse models (GEMMs) are crucial for studying SCLC pathogenesis and therapeutic development.
Purpose of the Study:
- To summarize the contributions of GEMMs to SCLC research over the past two decades.
- To review recent advancements in SCLC modeling, including CRISPR/Cas9 and allograft models.
- To highlight how new models facilitate the study of SCLC tumorigenesis and immune microenvironment interactions.
Main Methods:
- Development and utilization of genetically-engineered mouse models (GEMMs) with specific genetic alterations.
- Application of CRISPR/Cas9-mediated somatic gene editing for functional interrogation of genes in SCLC.
- Creation of allograft and precancerous precursor models from SCLC GEMMs.
Main Results:
- GEMMs have significantly advanced the understanding of SCLC biology and pathogenesis.
- CRISPR/Cas9 enables rapid functional analysis of novel genes in SCLC development.
- Allograft and precursor models offer complementary approaches to study tumor-immune interactions.
Conclusions:
- The evolution of SCLC models, particularly GEMMs and newer techniques, is critical for advancing SCLC research.
- Newer models overcome limitations of earlier GEMMs, enabling investigation of a broader range of genes.
- These innovative models are essential for discovering and testing novel therapeutic strategies to improve outcomes for SCLC patients.
