清脆的
基因组编辑
Cas9
生物
计算生物学
同源定向修复
引导RNA
基因组
基因组工程
转录激活物样效应核酸酶
基因
功能基因组学
基因组学
锌指核酸酶
DNA测序
亚基因组mRNA
遗传学
DNA修复
DNA错配修复
作者
Christopher H. Hulton,Emily A. Costa,Nisargbhai S. Shah,Álvaro Quintanal-Villalonga,Glenn Heller,Elisa de Stanchina,Charles M. Rudin,John T. Poirier
摘要
Patient-derived xenografts (PDXs) constitute a powerful set of preclinical models for in vivo cancer research, reflecting the spectrum of genomic alterations and therapeutic liabilities of human cancers 1-4 . In contrast to either cancer cell lines or genetically engineered mouse models, the utility of PDXs has been limited by the inability to perform targeted genome editing of these tumors. To address this limitation, we have generated a lentiviral platform for CRISPR-Cas9 editing of PDXs using a tightly regulated, inducible Cas9 vector that does not require in vitro culture for selection of transduced cells. We demonstrate the utility of this platform in PDXs (1) to analyze genetic dependencies by targeted gene disruption and (2) to analyze mechanisms of acquired drug resistance by site-specific gene editing using templated homology-directed repair. This flexible system has broad application to other explant models and substantially augments the utility of PDXs as genetically programmable models of human cancer.
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