In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis
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Author(s)
Taylor, Martin S.
Sicinska, Ewa T.
Suarez, Yvelisse
Yoo, James
Chen, Lillian
Zukerberg, Lawrence
Katajisto, Pekka
Deshpande, Vikram
Bass, Adam J.
Tsichlis, Philip N.
Date Issued
May 2017
Journal
Nature Biotechnology
Publisher
Nature Publishing Group
Citation
Roper, Jatin et al. “In Vivo Genome Editing and Organoid Transplantation Models of Colorectal Cancer and Metastasis.” Nature Biotechnology 35, 6 (May 2017): 569–576 © 2017 Nature America, Inc
Version
Author's final manuscript
Abstract
In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer (CRC) and metastasis, which rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations. Autochthonous tumor formation is induced by CRISPR-Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/ΔKras G12D/+ ;Trp53Δ/Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5 + stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1038/NBT.3836
