Research Article

Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer

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Science  13 Dec 2012:
DOI: 10.1126/science.1227670

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Intratumoral heterogeneity arises through evolution of genetically diverse subclones during tumor progression. However, whether cells within single genetic clones are functionally equivalent remains unknown. 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 on serial transplantation. Despite this stability, the proliferation, persistence, and chemotherapy tolerance of lentivirally marked lineages were variable within each clone. Chemotherapy promoted dominance of previously minor or dormant lineages. Thus, apart from genetic diversity, tumor cells display inherent functional variability in tumor propagation potential, a mechanism that contributes both to cancer growth and therapy tolerance.

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