Generation of precision preclinical cancer models using regulated in vivo base editing Journal Article
| Authors: | Katti, A.; Vega-Pérez, A.; Foronda, M.; Zimmerman, J.; Zafra, M. P.; Granowsky, E.; Goswami, S.; Gardner, E. E.; Diaz, B. J.; Simon, J. M.; Wuest, A.; Luan, W.; Fernandez, M. T. C.; Kadina, A. P.; Walker, J. A.; Holden, K.; Lowe, S. W.; Sánchez Rivera, F. J.; Dow, L. E. |
| Article Title: | Generation of precision preclinical cancer models using regulated in vivo base editing |
| Abstract: | Although single-nucleotide variants (SNVs) make up the majority of cancer-associated genetic changes and have been comprehensively catalogued, little is known about their impact on tumor initiation and progression. To enable the functional interrogation of cancer-associated SNVs, we developed a mouse system for temporal and regulatable in vivo base editing. The inducible base editing (iBE) mouse carries a single expression-optimized cytosine base editor transgene under the control of a tetracycline response element and enables robust, doxycycline-dependent expression across a broad range of tissues in vivo. Combined with plasmid-based or synthetic guide RNAs, iBE drives efficient engineering of individual or multiple SNVs in intestinal, lung and pancreatic organoids. Temporal regulation of base editor activity allows controlled sequential genome editing ex vivo and in vivo, and delivery of sgRNAs directly to target tissues facilitates generation of in situ preclinical cancer models. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2023. |
| Keywords: | immunohistochemistry; controlled study; protein expression; unclassified drug; single nucleotide polymorphism; genetics; missense mutation; nonhuman; neoplasm; neoplasms; pancreas; mouse; animal; animals; mice; allele; animal tissue; gene expression; amino acid substitution; green fluorescent protein; animal experiment; animal model; gene locus; in vivo study; heterozygote; protein p53; cancer model; histology; carcinogenesis; chimera; liver metastasis; genetic engineering; colon cancer; liver tumor; lung; transgene; immunoblotting; electroporation; gene control; ex-vivo; in-vivo; response elements; c57bl 6 mouse; tumor growth; doxycycline; ex vivo study; small intestine; tetracycline; stochastic model; transcriptome; colon; diseases; apc protein; fluorescence imaging; tissue; blastocyst; smad4 protein; cytosine; selumetinib; genetic changes; target tissues; rna editing; preclinical study; guide rna; cancer models; mendelian inheritance; phosphatidylinositol 4,5 bisphosphate 3 kinase; article; rna sequencing; differential gene expression; crispr cas system; organoids; gene editing; crispr-cas systems; malignant neoplasm; single guide rna; single nucleotides; base editing; temporal analysis; crispr associated endonuclease cas9; intestine tissue; collagen type i alpha 1 chain; rna, guide, crispr-cas systems; crispr-cas system guide rna; intestinal organoid; target tissue |
| Journal Title: | Nature Biotechnology |
| Volume: | 42 |
| Issue: | 3 |
| ISSN: | 1087-0156 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2024-03-01 |
| Start Page: | 437 |
| End Page: | 447 |
| Language: | English |
| DOI: | 10.1038/s41587-023-01900-x |
| PUBMED: | 37563300 |
| PROVIDER: | scopus |
| PMCID: | PMC11295146 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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