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Dickkopf1 Regulates Fate Decision and Drives Breast Cancer Stem Cells to Differentiation: An Experimentally Supported Mathematical Model

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  • Zvia Agur
  • Oleg U Kirnasovsky
  • Genadiy Vasserman
  • Lilach Tencer-Hershkowicz
  • Yuri Kogan
  • Hannah Harrison
  • Rebecca Lamb
  • Robert B Clarke

Abstract

Background: Modulation of cellular signaling pathways can change the replication/differentiation balance in cancer stem cells (CSCs), thus affecting tumor growth and recurrence. Analysis of a simple, experimentally verified, mathematical model suggests that this balance is maintained by quorum sensing (QS). Methodology/Principal Findings: To explore the mechanism by which putative QS cellular signals in mammary stem cells (SCs) may regulate SC fate decisions, we developed a multi-scale mathematical model, integrating extra-cellular and intra-cellular signal transduction within the mammary tissue dynamics. Preliminary model analysis of the single cell dynamics indicated that Dickkopf1 (Dkk1), a protein known to negatively regulate the Wnt pathway, can serve as anti-proliferation and pro-maturation signal to the cell. Simulations of the multi-scale tissue model suggested that Dkk1 may be a QS factor, regulating SC density on the level of the whole tissue: relatively low levels of exogenously applied Dkk1 have little effect on SC numbers, whereas high levels drive SCs into differentiation. To verify these model predictions, we treated the MCF-7 cell line and primary breast cancer (BC) cells from 3 patient samples with different concentrations and dosing regimens of Dkk1, and evaluated subsequent formation of mammospheres (MS) and the mammary SC marker CD44+CD24lo. As predicted by the model, low concentrations of Dkk1 had no effect on primary BC cells, or even increased MS formation among MCF-7 cells, whereas high Dkk1 concentrations decreased MS formation among both primary BC cells and MCF-7 cells. Conclusions/Significance: Our study suggests that Dkk1 treatment may be more robust than other methods for eliminating CSCs, as it challenges a general cellular homeostasis mechanism, namely, fate decision by QS. The study also suggests that low dose Dkk1 administration may be counterproductive; we showed experimentally that in some cases it can stimulate CSC proliferation, although this needs validating in vivo.

Suggested Citation

  • Zvia Agur & Oleg U Kirnasovsky & Genadiy Vasserman & Lilach Tencer-Hershkowicz & Yuri Kogan & Hannah Harrison & Rebecca Lamb & Robert B Clarke, 2011. "Dickkopf1 Regulates Fate Decision and Drives Breast Cancer Stem Cells to Differentiation: An Experimentally Supported Mathematical Model," PLOS ONE, Public Library of Science, vol. 6(9), pages 1-10, September.
  • Handle: RePEc:plo:pone00:0024225
    DOI: 10.1371/journal.pone.0024225
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    References listed on IDEAS

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    1. Tannishtha Reya & Hans Clevers, 2005. "Wnt signalling in stem cells and cancer," Nature, Nature, vol. 434(7035), pages 843-850, April.
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    Cited by:

    1. Sophie K Kay & Heather A Harrington & Sarah Shepherd & Keith Brennan & Trevor Dale & James M Osborne & David J Gavaghan & Helen M Byrne, 2017. "The role of the Hes1 crosstalk hub in Notch-Wnt interactions of the intestinal crypt," PLOS Computational Biology, Public Library of Science, vol. 13(2), pages 1-28, February.

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