Abstract
Variation in the growth dynamics of genetically stable clones modulates chemotherapy responses.
Major finding: Variation in the growth dynamics of genetically stable clones modulates chemotherapy responses.
Approach: The genetic and functional diversity of single colorectal cancer clones was assessed in mice.
Impact: Nongenetic factors also generate clonal heterogeneity and contribute to therapeutic tolerance.
Accumulation of genetic mutations in cancer gives rise to subclones with diverse growth and metastatic potentials. In addition, nongenetic factors, such as interactions with the tumor microenvironment and epigenetic changes, are thought to generate heterogeneity among genetically similar subclones, but it is not clear whether this results in functional differences in tumor propagation among individual cancer cells. To investigate this question in vivo, Kreso and colleagues tracked the fates of 150 GFP-labeled, single-cell–derived clonal lineages isolated from 10 primary human colorectal cancers through serially transplanted xenografts in mice. Copy number alteration profiling and sequencing of mutational hotspots demonstrated that xenografts remained genetically stable throughout serial transplantation and retained the genomic characteristics of the corresponding primary tumor. However, the clones exhibited significant functional variability in their repopulation and growth dynamics in multiple patient samples and could be classified into 5 types based on distinct patterns of emergence and longevity in sequential transplants: persistent, short-term, transient, and fluctuating clones, as well as resting clones that were initially dormant but initiated proliferation in later transplants. Mutational analysis confirmed the absence of genetic variability between different clone types isolated from the same tumor, suggesting that cells within a single genetic clone are functionally diverse. Intriguingly, these heterogeneous clone types also exhibited variable responses to chemotherapy, as treatment with oxaliplatin selectively decreased the proportion of persistent clones but promoted the dominant outgrowth of previously dormant, resting clones in secondary regrown tumors. This effect was independent of acquired genetic mutations in response to chemotherapy, underscoring the importance of nongenetic mechanisms in generating intratumoral heterogeneity. These results demonstrate that inherent functional diversity modulates colorectal cancer growth and therapeutic sensitivity and suggests that dormancy may be an adaptive mechanism used by tumors to facilitate tumor reinitiation after chemotherapy.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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