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CRISPR-mediated modeling and functional validation of candidate tumor suppressor genes in small cell lung cancer

ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive subtype of lung cancer that remains among the most lethal of solid tumor malignancies. Recent genomic sequencing studies have identified many recurrently mutated genes in human SCLC tumors. However, the functional roles of most of these genes remain to be validated. Here, we adapt the CRISPR-Cas9 system to a well-established murine model of SCLC to rapidly model loss-of-function mutations in candidate genes identified from SCLC sequencing studies. We show that loss of the gene p107 significantly accelerates tumor progression. Notably, compared with loss of the closely related gene p130, p107 loss results in fewer but larger tumors, as well as earlier metastatic spread. In addition, we observe differences in proliferation and apoptosis, as well as altered distribution of initiated tumors in the lung, resulting from loss of p107 or p130. Collectively, these data demonstrate the feasibility of using the CRISPR-Cas9 system to model loss of candidate tumor suppressor genes in SCLC, and we anticipate that this approach will greatly facilitate efforts to investigate mechanisms driving tumor progression in this deadly disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE139444 | GEO | 2019/12/19

REPOSITORIES: GEO

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