Many are called but few are chosen - Multiple clonal origins greatly elevate the functional heterogeneity of tumors
Chen, B.; Wu, X.; Ruan, Y.; Zhang, Y.; Wen, H.; Lan, P.; Wu, C.-I.
Show abstract
Each tumor is usually accepted to be of a single origin from a progenitor cell. The shared evolutionary paths impose a limit on the nature of genetic diversity of the tumor. However, there are also numerous stem cell niches with independent proliferation potentials. To reconcile the contrasting perspectives, we propose a model whereby each tumor is of multiple clonal origins but the most proliferative one would eclipse other minor clones. The detection of the minor clones would entail an extreme scheme of large-number but small-volume sampling. In two cases of colon tumors so sampled, one indeed has 13 independent clones of disparate sizes and even the smaller clones have tens of thousands of cells dispersed non-locally. The other, much larger, tumor has only one prevailing clone that engulfs two tiny patches of minor clones. In both cases, the expanding clone spawns a hierarchy of subclones that resemble vassal states on its wake of expansion. The timing of metastasis can also be mapped to the precise stage of the clonal expansion. In conclusion, multiple independent clones, likely common but difficult to detect, can greatly elevate the non-neutral diversity within a tumor. This much-elevated diversity has many theoretical and clinical implications.
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