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Heritable tumor cell division rate heterogeneity induces clonal dominance

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  • Margriet M Palm
  • Marjet Elemans
  • Joost B Beltman

Abstract

Tumors consist of a hierarchical population of cells that differ in their phenotype and genotype. This hierarchical organization of cells means that a few clones (i.e., cells and several generations of offspring) are abundant while most are rare, which is called clonal dominance. Such dominance also occurred in published in vitro iterated growth and passage experiments with tumor cells in which genetic barcodes were used for lineage tracing. A potential source for such heterogeneity is that dominant clones derive from cancer stem cells with an unlimited self-renewal capacity. Furthermore, ongoing evolution and selection within the growing population may also induce clonal dominance. To understand how clonal dominance developed in the iterated growth and passage experiments, we built a computational model that accurately simulates these experiments. The model simulations reproduced the clonal dominance that developed in in vitro iterated growth and passage experiments when the division rates vary between cells, due to a combination of initial variation and of ongoing mutational processes. In contrast, the experimental results can neither be reproduced with a model that considers random growth and passage, nor with a model based on cancer stem cells. Altogether, our model suggests that in vitro clonal dominance develops due to selection of fast-dividing clones.Author summary: Tumors consist of numerous cell populations, i.e., clones, that differ with respect to genotype, and potentially with respect to phenotype, and these populations strongly differ in their size. A limited number of clones tend to dominate tumors, but it remains unclear how this clonal dominance arises. Potential driving mechanisms are the presence of cancer stem cells, which either divide indefinitely of differentiate into cells with a limited division potential, and ongoing evolutionary processes within the tumor. Here we use a computational model to understand how clonal dominance developed during in vitro growth and passage experiments with cancer cells. Incorporating cancer stem cells in this model did not result in a match between simulations and in vitro data. In contrast, by considering all cells to divide indefinitely and division rates to evolve due to the combination of division rate variability and selection by passage, our model closely matches the in vitro data.

Suggested Citation

  • Margriet M Palm & Marjet Elemans & Joost B Beltman, 2018. "Heritable tumor cell division rate heterogeneity induces clonal dominance," PLOS Computational Biology, Public Library of Science, vol. 14(2), pages 1-19, February.
  • Handle: RePEc:plo:pcbi00:1005954
    DOI: 10.1371/journal.pcbi.1005954
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    References listed on IDEAS

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    1. Corbin E. Meacham & Sean J. Morrison, 2013. "Tumour heterogeneity and cancer cell plasticity," Nature, Nature, vol. 501(7467), pages 328-337, September.
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