Genetically-engineered mouse models of small cell lung cancer: the next generation.
Genetically-engineered mouse models of small cell lung cancer: the next generation.
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DOI：
10.1038/s41388-023-02929-7
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发表时间：
2024-01
期刊：
影响因子：
8
通讯作者：
M. Oser;D. MacPherson;T. Oliver;J. Sage;Kwon-Sik Park
中科院分区：
文献类型：
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作者：
M. Oser;D. MacPherson;T. Oliver;J. Sage;Kwon-Sik Park
小细胞肺癌（SCLC）仍然是最致命的肺癌形式，患者迫切需要新的有效治疗方法。在免疫活性宿主中建模SCLC对于理解SCLC发病机制并最终发现和测试新的实验治疗策略至关重要。人小细胞肺癌的特征是肿瘤抑制基因RB 1和TP 53几乎普遍缺失。20年前，第一个SCLC的基因工程小鼠模型（GEMM）是通过在成年小鼠的肺中同时删除Rb 1和Trp 53而产生的。从那时起，已经开发了几种其他的SCLC GEMM，将在人SCLC中发现的基因组改变与Rb 1和Trp 53缺失相结合。在这里，我们总结了如何GEMMs的小细胞肺癌作出了重大贡献，我们了解这种疾病在过去的二十年。我们还回顾了最近在小鼠SCLC建模方面的进展，这些进展使研究人员能够绕过上一代GEMM的限制，同时研究SCLC中感兴趣的新基因。特别是，CRISPR/Cas9介导的体细胞基因编辑可以加速在SCLC肿瘤发生中功能性询问新基因的方式。值得注意的是，从SCLC GEMM开发同种异体移植物模型和癌前体模型为GEMM提供了补充方法，以研究肿瘤细胞-免疫微环境相互作用并测试新的治疗策略以增强对免疫治疗的反应。最终，新一代SCLC模型可以加速研究并帮助开发新的SCLC治疗策略。
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 theRB1andTP53tumor suppressor genes. Twenty years ago, the first genetically-engineered mouse model (GEMM) of SCLC was generated using conditional deletion of bothRb1andTrp53in the lungs of adult mice. Since then, several other GEMMs of SCLC have been developed coupling genomic alterations found in human SCLC withRb1andTrp53deletion. 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.