Heritable tumor cell division rate heterogeneity induces clonal dominance

PLoS Comput Biol. 2018 Feb 12;14(2):e1005954. doi: 10.1371/journal.pcbi.1005954. eCollection 2018 Feb.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Division*
  • Clone Cells / cytology*
  • Computer Simulation
  • Genotype
  • HeLa Cells
  • Humans
  • K562 Cells
  • Likelihood Functions
  • Models, Biological
  • Mutation
  • Neoplasms / pathology*
  • Neoplastic Stem Cells / cytology*
  • Phenotype
  • Poisson Distribution
  • Sequence Analysis, DNA
  • Stochastic Processes

Grants and funding

This work was supported by the Netherlands Organisation for Scientific Research (https://www.nwo.nl/en); Vidi grant 864.12.013 to JBB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.