Genetic and transcriptional evolution alters cancer cell line drug response

被引:602
作者
Ben-David, Uri [1 ]
Siranosian, Benjamin [1 ]
Ha, Gavin [1 ,2 ]
Tang, Helen [1 ]
Oren, Yaara [1 ,3 ]
Hinohara, Kunihiko [1 ,2 ]
Strathdee, Craig A. [1 ]
Dempster, Joshua [1 ]
Lyons, Nicholas J. [1 ]
Burns, Robert [2 ]
Nag, Anwesha [2 ]
Kugener, Guillaume [1 ]
Cimini, Beth [1 ]
Tsvetkov, Peter [1 ]
Maruvka, Yosef E. [1 ]
O'Rourke, Ryan [1 ,2 ]
Garrity, Anthony [1 ]
Tubelli, Andrew A. [1 ]
Bandopadhayay, Pratiti [1 ,2 ,3 ]
Tsherniak, Aviad [1 ]
Vazquez, Francisca [1 ]
Wong, Bang [1 ]
Birger, Chet [1 ]
Ghandi, Mahmoud [1 ]
Thorner, Aaron R. [2 ]
Bittker, Joshua A. [1 ]
Meyerson, Matthew [1 ,2 ,3 ]
Getz, Gad [1 ,4 ]
Beroukhim, Rameen [1 ,2 ,3 ,5 ]
Golub, Todd R. [1 ,2 ,3 ,6 ]
机构
[1] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA
[2] Dana Farber Canc Inst, Boston, MA 02115 USA
[3] Harvard Med Sch, Boston, MA 02115 USA
[4] Massachusetts Gen Hosp, Boston, MA 02114 USA
[5] Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA
[6] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA
关键词
EXPRESSION; SENSITIVITY; DISCOVERY; DATABASE; REVEALS; SET; CLASSIFICATION; CONNECTIVITY; XENOGRAFTS; MUTATIONS;
D O I
10.1038/s41586-018-0409-3
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:325 / +
页数:31
相关论文
共 62 条
[21]   Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution [J].
Eirew, Peter ;
Steif, Adi ;
Khattra, Jaswinder ;
Ha, Gavin ;
Yap, Damian ;
Farahani, Hossein ;
Gelmon, Karen ;
Chia, Stephen ;
Mar, Colin ;
Wan, Adrian ;
Laks, Emma ;
Biele, Justina ;
Shumansky, Karey ;
Rosner, Jamie ;
McPherson, Andrew ;
Nielsen, Cydney ;
Roth, Andrew J. L. ;
Lefebvre, Calvin ;
Bashashati, Ali ;
de Souza, Camila ;
Siu, Celia ;
Aniba, Radhouane ;
Brimhall, Jazmine ;
Oloumi, Arusha ;
Osako, Tomo ;
Bruna, Alejandra ;
Sandoval, Jose L. ;
Algara, Teresa ;
Greenwood, Wendy ;
Leung, Kaston ;
Cheng, Hongwei ;
Xue, Hui ;
Wang, Yuzhuo ;
Lin, Dong ;
Mungall, Andrew J. ;
Moore, Richard ;
Zhao, Yongjun ;
Lorette, Julie ;
Long Nguyen ;
Huntsman, David ;
Eaves, Connie J. ;
Hansen, Carl ;
Marra, Marco A. ;
Caldas, Carlos ;
Shah, Sohrab P. ;
Aparicio, Samuel .
NATURE, 2015, 518 (7539) :422-426
[22]   A METHOD FOR COMPARING 2 HIERARCHICAL CLUSTERINGS [J].
FOWLKES, EB ;
MALLOWS, CL .
JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION, 1983, 78 (383) :553-569
[23]   The Economics of Reproducibility in Preclinical Research [J].
Freedman, Leonard P. ;
Cockburn, Iain M. ;
Simcoe, Timothy S. .
PLOS BIOLOGY, 2015, 13 (06) :1-9
[24]   Systematic identification of genomic markers of drug sensitivity in cancer cells [J].
Garnett, Mathew J. ;
Edelman, Elena J. ;
Heidorn, Sonja J. ;
Greenman, Chris D. ;
Dastur, Anahita ;
Lau, King Wai ;
Greninger, Patricia ;
Thompson, I. Richard ;
Luo, Xi ;
Soares, Jorge ;
Liu, Qingsong ;
Iorio, Francesco ;
Surdez, Didier ;
Chen, Li ;
Milano, Randy J. ;
Bignell, Graham R. ;
Tam, Ah T. ;
Davies, Helen ;
Stevenson, Jesse A. ;
Barthorpe, Syd ;
Lutz, Stephen R. ;
Kogera, Fiona ;
Lawrence, Karl ;
McLaren-Douglas, Anne ;
Mitropoulos, Xeni ;
Mironenko, Tatiana ;
Thi, Helen ;
Richardson, Laura ;
Zhou, Wenjun ;
Jewitt, Frances ;
Zhang, Tinghu ;
O'Brien, Patrick ;
Boisvert, Jessica L. ;
Price, Stacey ;
Hur, Wooyoung ;
Yang, Wanjuan ;
Deng, Xianming ;
Butler, Adam ;
Choi, Hwan Geun ;
Chang, JaeWon ;
Baselga, Jose ;
Stamenkovic, Ivan ;
Engelman, Jeffrey A. ;
Sharma, Sreenath V. ;
Delattre, Olivier ;
Saez-Rodriguez, Julio ;
Gray, Nathanael S. ;
Settleman, Jeffrey ;
Futreal, P. Andrew ;
Haber, Daniel A. .
NATURE, 2012, 483 (7391) :570-U87
[25]   Molecular classification of cancer: Class discovery and class prediction by gene expression monitoring [J].
Golub, TR ;
Slonim, DK ;
Tamayo, P ;
Huard, C ;
Gaasenbeek, M ;
Mesirov, JP ;
Coller, H ;
Loh, ML ;
Downing, JR ;
Caligiuri, MA ;
Bloomfield, CD ;
Lander, ES .
SCIENCE, 1999, 286 (5439) :531-537
[26]   Stochastic State Transitions Give Rise to Phenotypic Equilibrium in Populations of Cancer Cells [J].
Gupta, Piyush B. ;
Fillmore, Christine M. ;
Jiang, Guozhi ;
Shapira, Sagi D. ;
Tao, Kai ;
Kuperwasser, Charlotte ;
Lander, Eric S. .
CELL, 2011, 146 (04) :633-644
[27]   Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer [J].
Ha, Gavin ;
Roth, Andrew ;
Lai, Daniel ;
Bashashati, Ali ;
Ding, Jiarui ;
Goya, Rodrigo ;
Giuliany, Ryan ;
Rosner, Jamie ;
Oloumi, Arusha ;
Shumansky, Karey ;
Chin, Suet-Feung ;
Turashvili, Gulisa ;
Hirst, Martin ;
Caldas, Carlos ;
Marra, Marco A. ;
Aparicio, Samuel ;
Shah, Sohrab P. .
GENOME RESEARCH, 2012, 22 (10) :1995-2007
[28]   Inconsistency in large pharmacogenomic studies [J].
Haibe-Kains, Benjamin ;
El-Hachem, Nehme ;
Birkbak, Nicolai Juul ;
Jin, Andrew C. ;
Beck, Andrew H. ;
Aerts, Hugo J. W. L. ;
Quackenbush, John .
NATURE, 2013, 504 (7480) :389-+
[29]   Reproducible pharmacogenomic profiling of cancer cell line panels [J].
Haverty, Peter M. ;
Lin, Eva ;
Tan, Jenille ;
Yu, Yihong ;
Lam, Billy ;
Lianoglou, Steve ;
Neve, Richard M. ;
Artin, Scott M. ;
Ettleman, Jeff S. ;
Yauch, Robert L. ;
Bourgon, Richard .
NATURE, 2016, 533 (7603) :333-+
[30]   In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer [J].
Janiszewska, Michalina ;
Liu, Lin ;
Almendro, Vanessa ;
Kuang, Yanan ;
Paweletz, Cloud ;
Sakr, Rita A. ;
Weigelt, Britta ;
Hanker, Ariella B. ;
Chandarlapaty, Sarat ;
King, Tari A. ;
Reis-Filho, Jorge S. ;
Arteaga, Carlos L. ;
Park, So Yeon ;
Michor, Franziska ;
Polyak, Kornelia .
NATURE GENETICS, 2015, 47 (10) :1212-+