Genetic and transcriptional evolution alters cancer cell line drug response
Uri Ben-David,Benjamin A. Siranosian,Gavin Ha,Gavin Ha,Helen Tang,Yaara Oren,Yaara Oren,Kunihiko Hinohara,Kunihiko Hinohara,Craig A. Strathdee,Joshua M. Dempster,Nicholas J. Lyons,Robert Burns,Anwesha Nag,Guillaume Kugener,Beth A. Cimini,Peter Tsvetkov,Yosef E. Maruvka,Ryan O’Rourke,Ryan O’Rourke,Anthony J. Garrity,Andrew A. Tubelli,Pratiti Bandopadhayay,Pratiti Bandopadhayay,Aviad Tsherniak,Francisca Vazquez,Bang Wong,Chet Birger,Mahmoud Ghandi,Aaron R. Thorner,Joshua A. Bittker,Matthew Meyerson,Matthew Meyerson,Gad Getz,Gad Getz,Rameen Beroukhim,Todd R. Golub +36 more
TLDR
The extent, origins and consequences of genetic variation within human cell lines are studied, providing a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.Abstract:
Human cancer cell lines are the workhorse of cancer research. Although cell lines are known to evolve in culture, the extent of the resultant genetic and transcriptional heterogeneity and its functional consequences remain understudied. Here we use genomic analyses of 106 human cell lines grown in two laboratories to show extensive clonal diversity. Further comprehensive genomic characterization of 27 strains of the common breast cancer cell line MCF7 uncovered rapid genetic diversification. Similar results were obtained with multiple strains of 13 additional cell lines. Notably, genetic changes were associated with differential activation of gene expression programs and marked differences in cell morphology and proliferation. Barcoding experiments showed that cell line evolution occurs as a result of positive clonal selection that is highly sensitive to culture conditions. Analyses of single-cell-derived clones demonstrated that continuous instability quickly translates into heterogeneity of the cell line. When the 27 MCF7 strains were tested against 321 anti-cancer compounds, we uncovered considerably different drug responses: at least 75% of compounds that strongly inhibited some strains were completely inactive in others. This study documents the extent, origins and consequences of genetic variation within cell lines, and provides a framework for researchers to measure such variation in efforts to support maximally reproducible cancer research.read more
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Next-generation characterization of the Cancer Cell Line Encyclopedia
Mahmoud Ghandi,Franklin W. Huang,Franklin W. Huang,Franklin W. Huang,Judit Jané-Valbuena,Judit Jané-Valbuena,Gregory V. Kryukov,Christopher Lo,E. Robert McDonald,Jordi Barretina,Ellen Gelfand,Craig M. Bielski,Haoxin Li,Haoxin Li,Kevin Hu,Alexander Y. Andreev-Drakhlin,Jaegil Kim,Julian M. Hess,Brian J. Haas,François Aguet,Barbara A. Weir,Michael V. Rothberg,Brenton R. Paolella,Michael S. Lawrence,Rehan Akbani,Yiling Lu,Hong L. Tiv,Prafulla C. Gokhale,Antoine de Weck,Ali Amin Mansour,Coyin Oh,Juliann Shih,Kevin Hadi,Yanay Rosen,Jonathan Bistline,Kavitha Venkatesan,Anupama Reddy,Dmitriy Sonkin,Dmitriy Sonkin,Manway Liu,Joseph Lehar,Joshua M. Korn,Dale Porter,Michael D. Jones,Javad Golji,Giordano Caponigro,Jordan E. Taylor,Caitlin M. Dunning,Amanda L. Creech,Allison Warren,James M. McFarland,Mahdi Zamanighomi,Audrey Kauffmann,Nicolas Stransky,Marcin Imielinski,Yosef E. Maruvka,Yosef E. Maruvka,Andrew D. Cherniack,Andrew D. Cherniack,Aviad Tsherniak,Francisca Vazquez,Jacob D. Jaffe,Andrew A. Lane,David M. Weinstock,Cory M. Johannessen,Michael Morrissey,Frank Stegmeier,Robert Schlegel,William C. Hahn,William C. Hahn,Gad Getz,Gordon B. Mills,Jesse S. Boehm,Todd R. Golub,Todd R. Golub,Todd R. Golub,Levi A. Garraway,Levi A. Garraway,William R. Sellers,William R. Sellers +79 more
TL;DR: The original Cancer Cell Line Encyclopedia is expanded with deeper characterization of over 1,000 cell lines, including genomic, transcriptomic, and proteomic data, and integration with drug-sensitivity and gene-dependency data, which reveals potential targets for cancer drugs and associated biomarkers.
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq
Itay Tirosh,Benjamin Izar,Daniel J. Treacy,John J. Trombetta,Asaf Rotem,Christopher Rodman,Christine G. Lian,George F. Murphy,Mohammad Fallahi-Sichani,Ken Dutton-Regester,Jia-Ren Lin,Ofir Cohen,Parin Shah,Diana Lu,Alexandra-Chloé Villani,Aleksandr Andreev,E.M. Van Allen,Monica M. Bertagnolli,Peter K. Sorger,Ryan J. Sullivan,Keith T. Flaherty,Dennie T. Frederick,Judit Jané-Valbuena,Orit Rozenblatt-Rosen,Sanjay M. Prakadan,Marc H. Wadsworth,Alex S. Genshaft,Travis K. Hughes,Carly G. K. Ziegler,Samuel W. Kazer,Alethe Gaillard de Saint Germain,Kellie E. Kolb,Cory M. Johannessen,Clifford H. Yoon,Alex K. Shalek,Aviv Regev,Levi A. Garraway +36 more
TL;DR: Tirosh et al. as discussed by the authors applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells.
Journal ArticleDOI
Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials
Ann Lin,Ann Lin,Christopher J. Giuliano,Christopher J. Giuliano,Ann C. Palladino,Kristen M. John,Kristen M. John,Connor Abramowicz,Connor Abramowicz,Monet Lou Yuan,Erin L. Sausville,Devon A. Lukow,Devon A. Lukow,Luwei Liu,Luwei Liu,Alexander R. Chait,Zachary C. Galluzzo,Clara Tucker,Clara Tucker,Jason M. Sheltzer +19 more
TL;DR: It is suggested that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit.
Journal ArticleDOI
Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling.
Steven M. Corsello,Steven M. Corsello,Rohith T. Nagari,Ryan Spangler,Jordan Rossen,Mustafa Kocak,Jordan Bryan,Jordan Bryan,Ranad Humeidi,David Peck,Xiaoyun Wu,Anna Tang,Vickie M. Wang,Sam Bender,Evan Lemire,Rajiv Narayan,Philip Montgomery,Uri Ben-David,Uri Ben-David,Colin W. Garvie,Yii-Der Ida Chen,Matthew G. Rees,Nicholas J. Lyons,James M. McFarland,Bang Wong,Li Wang,Nancy Dumont,Patrick O'Hearn,Eric Stefan,Eric Stefan,John G. Doench,Caitlin N. Harrington,Heidi Greulich,Matthew Meyerson,Matthew Meyerson,Francisca Vazquez,Ayshwarya Subramanian,Jennifer Roth,Joshua Bittker,Joshua Bittker,Jesse S. Boehm,Christopher C. Mader,Aviad Tsherniak,Todd R. Golub +43 more
TL;DR: An unexpectedly large number of non-oncology drugs selectively inhibited subsets of cancer cell lines in a manner predictable from the cell lines' molecular features.
Journal ArticleDOI
Context is everything: aneuploidy in cancer
Uri Ben-David,Angelika Amon +1 more
TL;DR: The context dependency of aneuploidy in cancer is explained and its clinical potential is discussed, which may have clinical relevance as a prognostic marker and as a potential therapeutic target.
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