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Functional heterogeneity to chemotherapy occurs within subclones in colorectal cancer
▸ Kreso A, O'Brien CA, van Galen P, et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 2013;339:543–8.
It is becoming increasingly apparent that cancers are comprised of a population of genetically heterogeneous cells. This has given rise to the concept that chemoresistance or recurrence of cancers is dependent on the genetic makeup of specific subclones permitting regrowth of the tumour. This story has been complicated by the observation that even within cells of similar genotype, there are different responses to environmental pressures. Kreso and colleagues have been able to demonstrate that non-genetic factors contribute towards tumour growth by serial transplantation of single cell cloned cells extracted from 10 colorectal cancer patients into immunodeficient mice. Deep sequencing, DNA copy number alteration profiling and lentiviral (LV) lineage tracing revealed that primary xenografts were genetically representative of the primary colorectal cancer yet certain variants were found suggestive of the presence of subclones. The authors observed five types of distinct subclones after serial transplantations; type I LV clones that were present in all serial xenografts, type II clones that persisted through several xenografts but were not present in the final passage, type III LV clones that were present in the initial recipient but were not detected in any serial recipients, type IV LV clones that were undetected in the primary xenograft but were readily detectable in later xenografts and type V clones that demonstrated variable frequency through each xenograft. These data demonstrate convincing evidence that functionally distinct clones exist within monogenomic tumour cells. Oxaliplatin is a platinum based chemotherapy drug commonly used in the treatment of colorectal cancer. To determine the dynamics of each type of LV clone, oxaliplatin was administered to mice with genetically characterised primary but not to those with subsequent xenografted tumours. The …