Journal
SCIENCE
Volume 339, Issue 6119, Pages 543-548Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1227670
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Funding
- Genome Canada through the Ontario Genomics Institute
- Ontario Institute for Cancer Research
- Summit Award
- Canadian Institutes for Health Research
- Netherlands Organisation for Scientific Research
- NIH [R21 CA149990-01]
- Canada Research Chair
- Princess Margaret Hospital Foundation
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
- province of Ontario
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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.
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