Direct genome editing of patient-derived xenografts using CRISPR-Cas9 enables rapid in vivo functional genomics
- 29 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (3), 359-+
- https://doi.org/10.1038/s43018-020-0040-8
Abstract
Patient-derived xenografts (PDXs) are high-fidelity in vivo tumor models that accurately reflect many key aspects of human cancer. In contrast to 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 developed methods 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 to analyze genetic dependencies by targeted gene disruption and 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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (U24 CA213274, P01 CA129243, P30 CA008748, U01 CA199215, U24 CA213274, P01 CA129243)
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