Direct genome editing of patient-derived xenografts using CRISPR-Cas9 enables rapid in vivo functional genomics
Patient-derived xenografts are high fidelity in vivo tumor models that accurately reflect many key aspects of human cancer. 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 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 (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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:1 |
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| Enthalten in: |
Nature cancer - 1(2020), 3 vom: 11. März, Seite 359-369 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hulton, Christopher H [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.04.2022 Date Revised 22.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s43018-020-0040-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM319100286 |
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| 520 | |a Patient-derived xenografts are high fidelity in vivo tumor models that accurately reflect many key aspects of human cancer. 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 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 (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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Costa, Emily A |e verfasserin |4 aut | |
| 700 | 1 | |a Shah, Nisargbhai S |e verfasserin |4 aut | |
| 700 | 1 | |a Quintanal-Villalonga, Alvaro |e verfasserin |4 aut | |
| 700 | 1 | |a Heller, Glenn |e verfasserin |4 aut | |
| 700 | 1 | |a de Stanchina, Elisa |e verfasserin |4 aut | |
| 700 | 1 | |a Rudin, Charles M |e verfasserin |4 aut | |
| 700 | 1 | |a Poirier, John T |e verfasserin |4 aut | |
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