Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer

Overview

Journal Science

Specialty Science

Date 2012 Dec 15

PMID 23239622

Citations 384

Authors

Antonija Kreso

Catherine A OBrien

Peter van Galen

Olga I Gan

Faiyaz Notta

Andrew M K Brown

Karen Ng

Jing Ma

Erno Wienholds

Cyrille Dunant

Aaron Pollett

Steven Gallinger

John McPherson

Charles G Mullighan

Darryl Shibata

John E Dick

Affiliations

Soon will be listed here.

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.

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