A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- 1] Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario, Canada  Saskatchewan Cancer Agency, Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Improved efforts are necessary to define the functional product of cancer mutations currently being revealed through large-scale sequencing efforts. Using genome-scale pooled shRNA screening technology, we mapped negative genetic interactions across a set of isogenic cancer cell lines and confirmed hundreds of these interactions in orthogonal co-culture competition assays to generate a high-confidence genetic interaction network of differentially essential or differential essentiality (DiE) genes. The network uncovered examples of conserved genetic interactions, densely connected functional modules derived from comparative genomics with model systems data, functions for uncharacterized genes in the human genome and targetable vulnerabilities. Finally, we demonstrate a general applicability of DiE gene signatures in determining genetic dependencies of other non-isogenic cancer cell lines. For example, the PTEN(-/-) DiE genes reveal a signature that can preferentially classify PTEN-dependent genotypes across a series of non-isogenic cell lines derived from the breast, pancreas and ovarian cancers. Our reference network suggests that many cancer vulnerabilities remain to be discovered through systematic derivation of a network of differentially essential genes in an isogenic cancer cell model.
|Journal||Molecular Systems Biology|
|Publication status||Published - 8 Oct 2013|
- Breast Neoplasms, Cell Line, Tumor, Coculture Techniques, Epistasis, Genetic, Female, Gene Regulatory Networks, Genes, Essential, Genome, Human, Humans, Mutation, Neoplasm Proteins, Ovarian Neoplasms, PTEN Phosphohydrolase, Pancreatic Neoplasms, RNA, Small Interfering, Journal Article, Research Support, Non-U.S. Gov't