title: Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer.
abstract: 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.
authors.affiliation: Campbell Family Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
authors.forename: Antonija
authors.initials: A
authors.lastname: Kreso
authors.forename: Catherine A
authors.initials: CA
authors.lastname: O'Brien
authors.forename: Peter
authors.initials: P
authors.lastname: van Galen
authors.forename: Olga I
authors.initials: OI
authors.lastname: Gan
authors.forename: Faiyaz
authors.initials: F
authors.lastname: Notta
authors.forename: Andrew M K
authors.initials: AM
authors.lastname: Brown
authors.forename: Karen
authors.initials: K
authors.lastname: Ng
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Erno
authors.initials: E
authors.lastname: Wienholds
authors.forename: Cyrille
authors.initials: C
authors.lastname: Dunant
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: John
authors.initials: J
authors.lastname: McPherson
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Darryl
authors.initials: D
authors.lastname: Shibata
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000818:Animals; D019070:Cell Lineage; D058948:Cell Tracking; D060965:Clonal Evolution / Q000235:genetics*; D002999:Clone Cells; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D056915:DNA Copy Number Variations; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D016086:Lentivirus; D051379:Mice; D009368:Neoplasm Transplantation; D059467:Transcriptome; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured