Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer

被引:562
作者
Kreso, Antonija [1 ,2 ]
O'Brien, Catherine A. [1 ,3 ,4 ]
van Galen, Peter [1 ]
Gan, Olga I. [1 ]
Notta, Faiyaz [1 ,2 ]
Brown, Andrew M. K. [5 ]
Ng, Karen [5 ]
Ma, Jing [6 ]
Wienholds, Erno [1 ]
Dunant, Cyrille [7 ]
Pollett, Aaron [8 ]
Gallinger, Steven [9 ]
McPherson, John [5 ]
Mullighan, Charles G. [6 ]
Shibata, Darryl [10 ]
Dick, John E. [1 ,2 ]
机构
[1] Univ Hlth Network, Princess Margaret Canc Ctr, Ontario Canc Inst, Campbell Family Inst, Toronto, ON M5G 1L7, Canada
[2] Univ Toronto, Dept Mol Genet, Toronto, ON M5G 1L7, Canada
[3] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5L 1F4, Canada
[4] Univ Toronto, Dept Surg, Toronto, ON M5L 1F4, Canada
[5] Ontario Inst Canc Res, Toronto, ON M5G 1L7, Canada
[6] St Jude Childrens Res Hosp, Memphis, TN 38105 USA
[7] Univ Toronto, Dept Civil Engn, Toronto, ON M5S 1A4, Canada
[8] Mt Sinai Hosp, Dept Pathol, Toronto, ON M5G 1X5, Canada
[9] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred Litwin Ctr Canc Genet, Toronto, ON M7H 2B9, Canada
[10] Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA
关键词
ACUTE LYMPHOBLASTIC-LEUKEMIA; GENE-EXPRESSION; INITIATING CELLS; TUMOR-GROWTH; STEM-CELLS; EVOLUTION; ORIGINS; STOCHASTICITY; HETEROGENEITY; BIODIVERSITY;
D O I
10.1126/science.1227670
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
Intratumoral heterogeneity arises through the evolution of genetically diverse subclones during tumor progression. However, it remains unknown whether cells within single genetic clones are functionally equivalent. By combining DNA copy number alteration (CNA) profiling, sequencing, and lentiviral lineage tracking, we followed the repopulation dynamics of 150 single lentivirus-marked lineages from 10 human colorectal cancers through serial xenograft passages in mice. CNA and mutational analysis distinguished individual clones and showed that clones remained stable upon serial transplantation. Despite this stability, the proliferation, persistence, and chemotherapy tolerance of lentivirally marked lineages were variable within each clone. Chemotherapy promoted the dominance of previously minor or dormant lineages. Thus, apart from genetic diversity, tumor cells display inherent functional variability in tumor propagation potential, which contributes to both cancer growth and therapy tolerance.
引用
收藏
页码:543 / 548
页数:6
相关论文
共 30 条
[1]   LOCAL RECURRENCE OF COLORECTAL-CANCER - THE PROBLEM, MECHANISMS, MANAGEMENT AND ADJUVANT THERAPY [J].
ABULAFI, AM ;
WILLIAMS, NS .
BRITISH JOURNAL OF SURGERY, 1994, 81 (01) :7-19
[2]   Genetic variegation of clonal architecture and propagating cells in leukaemia [J].
Anderson, Kristina ;
Lutz, Christoph ;
van Delft, Frederik W. ;
Bateman, Caroline M. ;
Guo, Yanping ;
Colman, Susan M. ;
Kempski, Helena ;
Moorman, Anthony V. ;
Titley, Ian ;
Swansbury, John ;
Kearney, Lyndal ;
Enver, Tariq ;
Greaves, Mel .
NATURE, 2011, 469 (7330) :356-+
[3]   Context, tissue plasticity, and cancer: Are tumor stem cells also regulated by the microenvironment? [J].
Bissell, MJ ;
LaBarge, MA .
CANCER CELL, 2005, 7 (01) :17-23
[4]   Clonal selection in xenografted human T cell acute lymphoblastic leukemia recapitulates gain of malignancy at relapse [J].
Clappier, Emmanuelle ;
Gerby, Bastien ;
Sigaux, Francois ;
Delord, Marc ;
Touzri, Farah ;
Hernandez, Lucie ;
Ballerini, Paola ;
Baruchel, Andre ;
Pflumio, Francoise ;
Soulier, Jean .
JOURNAL OF EXPERIMENTAL MEDICINE, 2011, 208 (04) :653-661
[5]   Functional and phylogenetic diversity as predictors of biodiversity-ecosystem-function relationships [J].
Flynn, Dan F. B. ;
Mirotchnick, Nicholas ;
Jain, Meha ;
Palmer, Matthew I. ;
Naeem, Shahid .
ECOLOGY, 2011, 92 (08) :1573-1581
[6]   Noise minimization in eukaryotic gene expression [J].
Fraser, HB ;
Hirsh, AE ;
Giaever, G ;
Kumm, J ;
Eisen, MB .
PLOS BIOLOGY, 2004, 2 (06) :834-838
[7]   Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing [J].
Gerlinger, Marco ;
Rowan, Andrew J. ;
Horswell, Stuart ;
Larkin, James ;
Endesfelder, David ;
Gronroos, Eva ;
Martinez, Pierre ;
Matthews, Nicholas ;
Stewart, Aengus ;
Tarpey, Patrick ;
Varela, Ignacio ;
Phillimore, Benjamin ;
Begum, Sharmin ;
McDonald, Neil Q. ;
Butler, Adam ;
Jones, David ;
Raine, Keiran ;
Latimer, Calli ;
Santos, Claudio R. ;
Nohadani, Mahrokh ;
Eklund, Aron C. ;
Spencer-Dene, Bradley ;
Clark, Graham ;
Pickering, Lisa ;
Stamp, Gordon ;
Gore, Martin ;
Szallasi, Zoltan ;
Downward, Julian ;
Futreal, P. Andrew ;
Swanton, Charles .
NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (10) :883-892
[8]   Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification [J].
Gorre, ME ;
Mohammed, M ;
Ellwood, K ;
Hsu, N ;
Paquette, R ;
Rao, PN ;
Sawyers, CL .
SCIENCE, 2001, 293 (5531) :876-880
[9]   Clonal evolution in cancer [J].
Greaves, Mel ;
Maley, Carlo C. .
NATURE, 2012, 481 (7381) :306-313
[10]   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