Mapping a functional cancer genome atlas of tumor suppressors in mouse liver using AAV-CRISPR–mediated direct in vivo screening
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eaao5508.full.pdf
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Author(s)
Wang, Guangchuan
Chow, Ryan D.
Ye, Lupeng
Guzman, Christopher D.
Dai, Xiaoyun
Dong, Matthew B.
Zhang, Feng
Platt, Randall Jeffrey
Chen, Sidi
Sharp, Phillip A.
Date Issued
February 2018
Journal
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Wang, Guangchuan, Ryan D. Chow, Lupeng Ye, Christopher D. Guzman, Xiaoyun Dai, Matthew B. Dong, Feng Zhang, Phillip A. Sharp, Randall J. Platt, and Sidi Chen. “Mapping a Functional Cancer Genome Atlas of Tumor Suppressors in Mouse Liver Using AAV-CRISPR–mediated Direct in Vivo Screening.” Science Advances 4, no. 2 (February 2018): eaao5508.
Version
Final published version
Abstract
Cancer genomics consortia have charted the landscapes of numerous human cancers. Whereas somemutations were found in classical oncogenes and tumor suppressors, others have not yet been functionally studied in vivo. To date, a comprehensive assessment of how these genes influence oncogenesis is lacking. We performed direct highthroughput in vivo mapping of functional variants in an autochthonous mouse model of cancer. Using adenoassociated viruses (AAVs) carrying a single-guide RNA (sgRNA) library targeting putative tumor suppressor genes significantly mutated in human cancers, we directly pool-mutagenized the livers of Cre-inducible CRISPR (clustered regularly interspaced short palindromic repeats)-associated protein 9 (Cas9) mice. All mice that received the AAV-mTSG library developed liver cancer and diedwithin 4 months.We usedmolecular inversion probe sequencing of the sgRNA target sites to chart the mutational landscape of these tumors, revealing the functional consequence of multiple variants in driving liver tumorigenesis in immunocompetent mice. AAV-mediated autochthonous CRISPR screens provide a powerful means for mapping a provisional functional cancer genome atlas of tumor suppressors in vivo.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
McGovern Institute for Brain Research at MIT
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial 4.0 International
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DOI of Published Version
https://doi.org/10.1126/SCIADV.AAO5508
