清脆的
癌变
Cas9
突变
生物
基因
肺癌
PTEN公司
计算生物学
癌症研究
突变
遗传学
医学
病理
细胞凋亡
PI3K/AKT/mTOR通路
作者
Irene Lara‐Sáez,Ángeles Mencía,Enrique Recuero,Yinghao Li,Marta García,Marta Oteo,Marta I. Gallego,Ana B. Enguita,Diana de Prado-Verdún,A Sigen,Wenxin Wang,Ramón Garcı́a-Escudero,Rodolfo Murillas,Mirentxu Santos
标识
DOI:10.1073/pnas.2322917121
摘要
Functional analysis in mouse models is necessary to establish the involvement of a set of genetic variations in tumor development. A modeling platform to facilitate and cost-effectively analyze the role of multiple genes in carcinogenesis would be valuable. Here, we present an innovative strategy for lung mutagenesis using CRISPR/Cas9 ribonucleoproteins delivered via cationic polymers. This approach allows the simultaneous inactivation of multiple genes. We validate the effectiveness of this system by targeting a group of tumor suppressor genes, specifically Rb1 , Rbl1 , Pten , and Trp53 , which were chosen for their potential to cause lung tumors, namely small cell lung carcinoma (SCLC). Tumors with histologic and transcriptomic features of human SCLC emerged after intratracheal administration of CRISPR/polymer nanoparticles. These tumors carried loss-of-function mutations in all four tumor suppressor genes at the targeted positions. These findings were reproduced in two different pure genetic backgrounds. We provide a proof of principle for simplified modeling of lung tumorigenesis to facilitate functional testing of potential cancer-related genes.
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