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Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer

2012; American Association for the Advancement of Science; Volume: 339; Issue: 6119 Linguagem: Inglês

10.1126/science.1227670

1095-9203

Antonija Kreso, Catherine O’Brien, Peter van Galen, Olga I. Gan, Faiyaz Notta, Andrew Brown, K.T. Ng, Jing Ma, Erno Wienholds, Cyrille F. Dunant, Aaron Pollett, Steven Gallinger, John D. McPherson, Charles G. Mullighan, Darryl Shibata, John E. Dick,

Molecular Biology Techniques and Applications

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.