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Cell DOI:10.1016/j.cell.2015.02.038

Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis.

Publication TypeJournal Article
Year of Publication2015
AuthorsChen, S, Sanjana, NE, Zheng, K, Shalem, O, Lee, K, Shi, X, Scott, DA, Song, J, Pan, JQ, Weissleder, R, Lee, H, Zhang, F, Sharp, PA
Date Published2015 Mar 12
KeywordsAnimals, Carcinoma, Non-Small-Cell Lung, CRISPR-Cas Systems, Gene Knockout Techniques, Genome-Wide Association Study, Humans, Lung Neoplasms, Mice, Neoplasm Metastasis, RNA, Guide

Genetic screens are powerful tools for identifying genes responsible for diverse phenotypes. Here we describe a genome-wide CRISPR/Cas9-mediated loss-of-function screen in tumor growth and metastasis. We mutagenized a non-metastatic mouse cancer cell line using a genome-scale library with 67,405 single-guide RNAs (sgRNAs). The mutant cell pool rapidly generates metastases when transplanted into immunocompromised mice. Enriched sgRNAs in lung metastases and late-stage primary tumors were found to target a small set of genes, suggesting that specific loss-of-function mutations drive tumor growth and metastasis. Individual sgRNAs and a small pool of 624 sgRNAs targeting the top-scoring genes from the primary screen dramatically accelerate metastasis. In all of these experiments, the effect of mutations on primary tumor growth positively correlates with the development of metastases. Our study demonstrates Cas9-based screening as a robust method to systematically assay gene phenotypes in cancer evolution in vivo.


Alternate JournalCell
PubMed ID25748654
PubMed Central IDPMC4380877
Grant ListR01-CA133404 / CA / NCI NIH HHS / United States
U54 CA151884 / CA / NCI NIH HHS / United States
K99 HG008171 / HG / NHGRI NIH HHS / United States
5DP1-MH100706 / DP / NCCDPHP CDC HHS / United States
P01 CA042063 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
K99-HG008171 / HG / NHGRI NIH HHS / United States
R01 CA133404 / CA / NCI NIH HHS / United States
DP1 MH100706 / MH / NIMH NIH HHS / United States
R01 DK097768 / DK / NIDDK NIH HHS / United States
5R01-DK097768 / DK / NIDDK NIH HHS / United States