Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer

TLDR: Combining DNA copy number alteration (CNA) profiling, sequencing, and lentiviral lineage tracking, this work followed the repopulation dynamics of 150 single lentivirus-marked lineages from 10 human colorectal cancers through serial xenograft passages in mice, showing that clones remained stable upon serial transplantation and Chemotherapy promoted the dominance of previously minor or dormant lineages.

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