Molecular Systems Biology (Jan 2013)
A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities
- Franco J Vizeacoumar,
- Roland Arnold,
- Frederick S Vizeacoumar,
- Megha Chandrashekhar,
- Alla Buzina,
- Jordan T F Young,
- Julian H M Kwan,
- Azin Sayad,
- Patricia Mero,
- Steffen Lawo,
- Hiromasa Tanaka,
- Kevin R Brown,
- Anastasia Baryshnikova,
- Anthony B Mak,
- Yaroslav Fedyshyn,
- Yadong Wang,
- Glauber C Brito,
- Dahlia Kasimer,
- Taras Makhnevych,
- Troy Ketela,
- Alessandro Datti,
- Mohan Babu,
- Andrew Emili,
- Laurence Pelletier,
- Jeff Wrana,
- Zev Wainberg,
- Philip M Kim,
- Robert Rottapel,
- Catherine A O'Brien,
- Brenda Andrews,
- Charles Boone,
- Jason Moffat
Affiliations
- Franco J Vizeacoumar
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Roland Arnold
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Frederick S Vizeacoumar
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto Ontario Canada
- Megha Chandrashekhar
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Alla Buzina
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Jordan T F Young
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto Ontario Canada
- Julian H M Kwan
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Azin Sayad
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Patricia Mero
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Steffen Lawo
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto Ontario Canada
- Hiromasa Tanaka
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Kevin R Brown
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Anastasia Baryshnikova
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Anthony B Mak
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Yaroslav Fedyshyn
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Yadong Wang
- Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network Toronto Ontario Canada
- Glauber C Brito
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Dahlia Kasimer
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Taras Makhnevych
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Troy Ketela
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Alessandro Datti
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto Ontario Canada
- Mohan Babu
- Department of Biochemistry, Research and Innovation Centre, University of Regina Regina Saskatchewan Canada
- Andrew Emili
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Laurence Pelletier
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto Ontario Canada
- Jeff Wrana
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital Toronto Ontario Canada
- Zev Wainberg
- Jonnson Comprehensive Cancer Center, Geffen School of Medicine, University of California at Los Angeles Los Angeles California USA
- Philip M Kim
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Robert Rottapel
- Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network Toronto Ontario Canada
- Catherine A O'Brien
- Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network Toronto Ontario Canada
- Brenda Andrews
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Charles Boone
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- Jason Moffat
- Donnelly Centre and Banting and Best Department of Medical Research, University of Toronto Toronto Ontario Canada
- DOI
- https://doi.org/10.1038/msb.2013.54
- Journal volume & issue
-
Vol. 9,
no. 1
pp. n/a – n/a
Abstract
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.
Keywords