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

doi:10.1038/msb.2013.54

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 KetelaAlessandro 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

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

57 Citations (Scopus)

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.

Original language	English
Pages (from-to)	696
Journal	Molecular Systems Biology
Volume	9
DOIs	https://doi.org/10.1038/msb.2013.54
Publication status	Published - 8 Oct 2013

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/msb.2013.54

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Vizeacoumar, F. J., Arnold, R., Vizeacoumar, F. S., Chandrashekhar, M., Buzina, A., Young, J. T. F., Kwan, J. H. M., Sayad, A., Mero, P., Lawo, S., Tanaka, H., Brown, K. R., Baryshnikova, A., Mak, A. B., Fedyshyn, Y., Wang, Y., Brito, G. C., Kasimer, D., Makhnevych, T., ... Moffat, J. (2013). A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities. Molecular Systems Biology, 9, 696. https://doi.org/10.1038/msb.2013.54

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title = "A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities",

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 = "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",

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Vizeacoumar, FJ, Arnold, R, Vizeacoumar, FS, Chandrashekhar, M, Buzina, A, Young, JTF, Kwan, JHM, Sayad, A, Mero, P, Lawo, S, Tanaka, H, Brown, KR, Baryshnikova, A, Mak, AB, Fedyshyn, Y, Wang, Y, Brito, GC, Kasimer, D, Makhnevych, T, Ketela, T, Datti, A, Babu, M, Emili, A, Pelletier, L, Wrana, J, Wainberg, Z, Kim, PM, Rottapel, R, O'Brien, CA, Andrews, B, Boone, C & Moffat, J 2013, 'A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities', Molecular Systems Biology, vol. 9, pp. 696. https://doi.org/10.1038/msb.2013.54

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AU - Vizeacoumar, Franco J

AU - Arnold, Roland

AU - Vizeacoumar, Frederick S

AU - Chandrashekhar, Megha

AU - Buzina, Alla

AU - Young, Jordan T F

AU - Kwan, Julian H M

AU - Sayad, Azin

AU - Mero, Patricia

AU - Lawo, Steffen

AU - Tanaka, Hiromasa

AU - Brown, Kevin R

AU - Baryshnikova, Anastasia

AU - Mak, Anthony B

AU - Fedyshyn, Yaroslav

AU - Wang, Yadong

AU - Brito, Glauber C

AU - Kasimer, Dahlia

AU - Makhnevych, Taras

AU - Ketela, Troy

AU - Datti, Alessandro

AU - Babu, Mohan

AU - Emili, Andrew

AU - Pelletier, Laurence

AU - Wrana, Jeff

AU - Wainberg, Zev

AU - Kim, Philip M

AU - Rottapel, Robert

AU - O'Brien, Catherine A

AU - Andrews, Brenda

AU - Boone, Charles

AU - Moffat, Jason

PY - 2013/10/8

Y1 - 2013/10/8

N2 - 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.

AB - 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.

KW - Breast Neoplasms

KW - Cell Line, Tumor

KW - Coculture Techniques

KW - Epistasis, Genetic

KW - Female

KW - Gene Regulatory Networks

KW - Genes, Essential

KW - Genome, Human

KW - Humans

KW - Mutation

KW - Neoplasm Proteins

KW - Ovarian Neoplasms

KW - PTEN Phosphohydrolase

KW - Pancreatic Neoplasms

KW - RNA, Small Interfering

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/msb.2013.54

DO - 10.1038/msb.2013.54

M3 - Article

C2 - 24104479

SN - 1744-4292

VL - 9

SP - 696

JO - Molecular Systems Biology

JF - Molecular Systems Biology

ER -

A negative genetic interaction map in isogenic cancer cell lines reveals cancer cell vulnerabilities

Abstract

Keywords

UN SDGs

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