title: Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.
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).
  
  
  RESULTS
  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(+)CD24(lo). 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
  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.
authors.affiliation: Institute for Medical BioMathematics, Bene Ataroth, Israel. agur@imbm.org
authors.forename: Zvia
authors.initials: Z
authors.lastname: Agur
authors.forename: Oleg U
authors.initials: OU
authors.lastname: Kirnasovsky
authors.forename: Genadiy
authors.initials: G
authors.lastname: Vasserman
authors.forename: Lilach
authors.initials: L
authors.lastname: Tencer-Hershkowicz
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kogan
authors.forename: Hannah
authors.initials: H
authors.lastname: Harrison
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lamb
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008962:Models, Theoretical; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D051927:CD24 Antigen; C501126:DKK1 protein, human; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; C106075:NOTCH4 protein, human; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D051880:Receptors, Notch