Genome-Wide CRISPR Screen Provides Better Understanding of Tumor Evolution and Metastasis
Scientists from the Broad Institute and the Koch Institute for Integrative Cancer Research at MIT used CRISPR-Cas9 gene-editing technology to “knock out,” or turn off, all genes across the genome systematically in a mouse model of non–small cell lung cancer cells and then tested how the genes affect tumor growth and metastasis. The study provides a better understanding of how tumors evolve over time and could result in better prevention and diagnostic strategies and more targeted therapies for cancer. The study by Chen et al is published in Cell.
Study Methodology
CRISPR-Cas9 gene-editing technology enables scientists to investigate the role of genes and genetic mutations in human biology and disease. The system can remove the function of genes at the DNA level. In this study, cells from a mouse model of non–small cell lung cancer were treated with the Broad Institute’s genome-scale library of CRISPR guide RNAs targeting every gene in the mouse genome along with the Cas9 DNA-cutting enzyme.
The system introduces mutations into specific genes, disrupting their sequence and preventing the production of proteins from those genes.
Study Findings
The researchers then transplanted the cells into a mouse and found that the cells treated with the knockout library formed highly metastatic tumors. Using next-generation sequencing, the scientists were able to identify which genes were knocked out in the primary tumors and in the metastases, suggesting that the genes are likely tumor suppressors that normally inhibit tumor growth, but when knocked out, promote it.
The study results highlighted some well-known tumor-suppressor genes in human cancer, including PTEN, CDKN2A, and NF2, and included some genes not previously linked to cancer. The screen also implicated several microRNAs.
“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,” concluded the researchers.
Feng Zhang, PhD, and Philip A. Sharp, PhD, of the Massachusetts Institute of Technology, are the corresponding authors for the Cell article.
Funding for this study was provided by the National Institutes of Health, the U.S. Department of Defense, Marie D. and Pierre Casimir-Lambert Fund, Skolkovo Foundation, National Science Foundation, Keck Foundation, New York Stem Cell Foundation, Damon Runyon Foundation, Searle Scholars Foundation, Merkin Foundation, Vallee Foundation, Dale Frey Award for Breakthrough Scientists, and the Simons Center for the Social Brain.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
