Genetic and transcriptional evolution alters cancer cell line drug response

被引：604

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

来源：

NATURE | 2018年 / 560卷 / 7718期

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

页码：325 / +

页数：31

共 62 条

[1] BreaKmer: detection of structural variation in targeted massively parallel sequencing data using kmers [J].

Abo, Ryan P. ;

Ducar, Matthew ;

Garcia, Elizabeth P. ;

Thorner, Aaron R. ;

Rojas-Rudilla, Vanesa ;

Lin, Ling ;

Sholl, Lynette M. ;

Hahn, William C. ;

Meyerson, Matthew ;

Lindeman, Neal I. ;

Van Hummelen, Paul ;

MacConaill, Laura E. .

NUCLEIC ACIDS RESEARCH, 2015, 43 (03)

[2] Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors [J].

Adalsteinsson, Viktor A. ;

Ha, Gavin ;

Freeman, Samuel S. ;

Choudhury, Atish D. ;

Stover, Daniel G. ;

Parsons, Heather A. ;

Gydush, Gregory ;

Reed, Sarah C. ;

Rotem, Denisse ;

Rhoades, Justin ;

Loginov, Denis ;

Livitz, Dimitri ;

Rosebrock, Daniel ;

Leshchiner, Ignaty ;

Kim, Jaegil ;

Stewart, Chip ;

Rosenberg, Mara ;

Francis, Joshua M. ;

Zhang, Cheng-Zhong ;

Cohen, Ofir ;

Oh, Coyin ;

Ding, Huiming ;

Polak, Paz ;

Lloyd, Max ;

Mahmud, Sairah ;

Helvie, Karla ;

Merrill, Margaret S. ;

Santiago, Rebecca A. ;

O'Connor, Edward P. ;

Jeong, Seong H. ;

Leeson, Rachel ;

Barry, Rachel M. ;

Kramkowski, Joseph F. ;

Zhang, Zhenwei ;

Polacek, Laura ;

Lohr, Jens G. ;

Schleicher, Molly ;

Lipscomb, Emily ;

Saltzman, Andrea ;

Oliver, Nelly M. ;

Marini, Lori ;

Waks, Adrienne G. ;

Harshman, Lauren C. ;

Tolaney, Sara M. ;

Van Allen, Eliezer M. ;

Winer, Eric P. ;

Lin, Nancy U. ;

Nakabayashi, Mari ;

Taplin, Mary-Ellen ;

Johannessen, Cory M. .

NATURE COMMUNICATIONS, 2017, 8

[3] The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website [J].

Bamford, S ;

Dawson, E ;

Forbes, S ;

Clements, J ;

Pettett, R ;

Dogan, A ;

Flanagan, A ;

Teague, J ;

Futreal, PA ;

Stratton, MR ;

Wooster, R .

BRITISH JOURNAL OF CANCER, 2004, 91 (02) :355-358

[4] Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 [J].

Barbie, David A. ;

Tamayo, Pablo ;

Boehm, Jesse S. ;

Kim, So Young ;

Moody, Susan E. ;

Dunn, Ian F. ;

Schinzel, Anna C. ;

Sandy, Peter ;

Meylan, Etienne ;

Scholl, Claudia ;

Froehling, Stefan ;

Chan, Edmond M. ;

Sos, Martin L. ;

Michel, Kathrin ;

Mermel, Craig ;

Silver, Serena J. ;

Weir, Barbara A. ;

Reiling, Jan H. ;

Sheng, Qing ;

Gupta, Piyush B. ;

Wadlow, Raymond C. ;

Le, Hanh ;

Hoersch, Sebastian ;

Wittner, Ben S. ;

Ramaswamy, Sridhar ;

Livingston, David M. ;

Sabatini, David M. ;

Meyerson, Matthew ;

Thomas, Roman K. ;

Lander, Eric S. ;

Mesirov, Jill P. ;

Root, David E. ;

Gilliland, D. Gary ;

Jacks, Tyler ;

Hahn, William C. .

NATURE, 2009, 462 (7269) :108-U122

[5] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[6] An Interactive Resource to Identify Cancer Genetic and Lineage Dependencies Targeted by Small Molecules [J].

Basu, Amrita ;

Bodycombe, Nicole E. ;

Cheah, Jaime H. ;

Price, Edmund V. ;

Liu, Ke ;

Schaefer, Giannina I. ;

Ebright, Richard Y. ;

Stewart, Michelle L. ;

Ito, Daisuke ;

Wang, Stephanie ;

Bracha, Abigail L. ;

Liefeld, Ted ;

Wawer, Mathias ;

Gilbert, Joshua C. ;

Wilson, Andrew J. ;

Stransky, Nicolas ;

Kryukov, Gregory V. ;

Dancik, Vlado ;

Barretina, Jordi ;

Garraway, Levi A. ;

Hon, C. Suk-Yee ;

Munoz, Benito ;

Bittker, Joshua A. ;

Stockwell, Brent R. ;

Khabele, Dineo ;

Stern, Andrew M. ;

Clemons, Paul A. ;

Shamji, Alykhan F. ;

Schreiber, Stuart L. .

CELL, 2013, 154 (05) :1151-1161

[7] Patient-derived xenografts undergo mouse-specific tumor evolution [J].

Ben-David, Uri ;

Ha, Gavin ;

Tseng, Yuen-Yi ;

Greenwald, Noah F. ;

Oh, Coyin ;

Shih, Juliann ;

McFarland, James M. ;

Wong, Bang ;

Boehm, Jesse S. ;

Beroukhim, Rameen ;

Golub, Todd R. .

NATURE GENETICS, 2017, 49 (11) :1567-+

[8] Virtual karyotyping of pluripotent stem cells on the basis of their global gene expression profiles [J].

Ben-David, Uri ;

Mayshar, Yoav ;

Benvenisty, Nissim .

NATURE PROTOCOLS, 2013, 8 (05) :989-997

[9] High-throughput Phenotyping of Lung Cancer Somatic Mutations [J].

Berger, Alice H. ;

Brooks, Angela N. ;

Wu, Xiaoyun ;

Shrestha, Yashaswi ;

Chouinard, Candace ;

Piccioni, Federica ;

Bagul, Mukta ;

Kamburov, Atanas ;

Imielinski, Marcin ;

Hogstrom, Larson ;

Zhu, Cong ;

Yang, Xiaoping ;

Pantel, Sasha ;

Sakai, Ryo ;

Watson, Jacqueline ;

Kaplan, Nathan ;

Campbell, Joshua D. ;

Singh, Shantanu ;

Root, David E. ;

Narayan, Rajiv ;

Natoli, Ted ;

Lahr, David L. ;

Tirosh, Itay ;

Tamayo, Pablo ;

Getz, Gad ;

Wong, Bang ;

Doench, John ;

Subramanian, Aravind ;

Golub, Todd R. ;

Meyerson, Matthew ;

Boehm, Jesse S. .

CANCER CELL, 2016, 30 (02) :214-228

[10] Studying clonal dynamics in response to cancer therapy using high-complexity barcoding [J].

Bhang, Hyo-eun C. ;

Ruddy, David A. ;

Radhakrishna, Viveksagar Krishnamurthy ;

Caushi, Justina X. ;

Zhao, Rui ;

Hims, Matthew M. ;

Singh, Angad P. ;

Kao, Iris ;

Rakiec, Daniel ;

Shaw, Pamela ;

Balak, Marissa ;

Raza, Alina ;

Ackley, Elizabeth ;

Keen, Nicholas ;

Schlabach, Michael R. ;

Palmer, Michael ;

Leary, Rebecca J. ;

Chiang, Derek Y. ;

Sellers, William R. ;

Michor, Franziska ;

Cooke, Vesselina G. ;

Korn, Joshua M. ;

Stegmeier, Frank .

NATURE MEDICINE, 2015, 21 (05) :440-U207

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