Journal
CELL
Volume 160, Issue 6, Pages 1246-1260Publisher
CELL PRESS
DOI: 10.1016/j.cell.2015.02.038
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Funding
- United States Public Health Service from the NIH [R01-CA133404]
- MIT-Harvard Center for Cancer Nanotechnology Excellence from the National Cancer Institute [U54 CA151884]
- Skolkovo Foundation
- Koch Institute from the National Cancer Institute [P30-CA14051]
- NIH through NIMH [5DP1-MH100706]
- NIDDK [5R01-DK097768]
- National Science Foundation
- Keck foundation
- New York Stem Cell foundation
- Damon Runyon foundation
- Searle Scholars foundation
- Merkin foundation
- Vallee foundation
- Bob Metcalfe
- Dale Frey Award for Breakthrough Scientists
- Simons Center for the Social Brain Postdoctoral Fellowship
- NIH NHGRI [K99-HG008171]
- NIH [U54 CA151884]
- NSF
- Department of Defense [OCRP W81XWH-14-1-0279]
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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.
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