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 that 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/Δ;KrasG12D/+;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. Citation Format: Jatin Roper, Tuomas Tammela, Naniye Malli Cetinbas, Adam Akkad, Ali Roghanian, Steffen Rickelt, Mohammad Almeqdadi, Katherine Wu, Matthias Oberli, Francisco Sanchez-Rivera, Yoona Park, Xu Liang, George Eng, Martin S. Taylor, Roxana Azimi, Dmitriy Kedrin, Rachit Neupane, Semir Beyaz, Ewa T. Sicinska, Yvelisse Suarez, James Yoo, Lillian Chen, Lawrence Zukerberg, Pekka Katajisto, Vikram Deshpande, Adam Bass, Philip N. Tsichlis, Jacqueline Lees, Robert Langer, Richard O. Hynes, Jianzhu Chen, Arjun J. Bhutkar, Tyler Jacks, Omer H. Yilmaz. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B38.

Abstract B38: In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis

The adaptive immune systems of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated genes (Cas) selectively destroy nonnative DNA and defend almost all archaea and about half of the bacteria against infections. In the past years, the system has been genetically engineered to a powerful genome editing tool for a wide variety of organisms. Recently, many progresses have been made in the CRISPR-Cas systems. These improvements include applications in editing multiple genes, correcting mutation genes with one base difference, targeting nondividing cells, reducing off-target, and editing RNAs. The biomedical applications of the technology are to edit not only cells but also embryos in clinical settings. In this review, we briefly introduce the improvements of CRISPR-Cas9 gene editing methods and summarize the recent advances of this technology.

Recent progress in technological improvement and biomedical applications of the clustered regularly interspaced short palindromic repeats/cas system

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Recent progress in technological improvement and biomedical applications of the clustered regularly interspaced short palindromic repeats/cas system