Operating principles of Notch–Delta–Jagged module of cell–cell communication

Notch pathway is an evolutionarily conserved cell–cell communication mechanism governing cell-fate during development and tumor progression. It is activated when Notch receptor of one cell binds to either of its ligand—Delta or Jagged—of another cell. Notch–Delta (ND) signaling forms a two-way switch, and two cells interacting via ND signaling adopt different fates—Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Notch–Delta–Jagged signaling (NDJ) behaves as a three-way switch and enables an additional fate—hybrid Sender/Receiver (S/R) (medium ligand, medium receptor). Here, by extending our framework of NDJ signaling for a two-cell system, we show that higher production rate of Jagged, but not that of Delta, expands the range of parameters for which both cells attain the hybrid S/R state. Conversely, glycosyltransferase Fringe and cis-inhibition reduces this range of conditions, and reduces the relative stability of the hybrid S/R state, thereby promoting cell-fate divergence and consequently lateral inhibition-based patterns. Lastly, soluble Jagged drives the cells to attain the hybrid S/R state, and soluble Delta drives them to be Receivers. We also discuss the critical role of hybrid S/R state in promoting cancer metastasis by enabling collective cell migration and expanding cancer stem cell (CSC) population.

[1]  H. Ford,et al.  Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression , 2010, Journal of Mammary Gland Biology and Neoplasia.

[2]  S. Lipkin,et al.  NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. , 2010, Cancer research.

[3]  Dongyu Jia,et al.  Cis-interactions between Notch and its ligands block ligand-independent Notch activity , 2014, eLife.

[4]  J. Gale,et al.  Delta-like 1 and lateral inhibition during hair cell formation in the chicken inner ear: evidence against cis-inhibition , 2012, Development.

[5]  Eshel Ben-Jacob,et al.  Modeling putative therapeutic implications of exosome exchange between tumor and immune cells , 2014, Proceedings of the National Academy of Sciences.

[6]  Zhiwei Wang,et al.  Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. , 2009, Cancer research.

[7]  G. Pizzolo,et al.  Role of stromal cell-mediated Notch signaling in CLL resistance to chemotherapy , 2012, Blood Cancer Journal.

[8]  Eshel Ben-Jacob,et al.  Construction of an effective landscape for multistate genetic switches. , 2014, Physical review letters.

[9]  Cecilia Clementi,et al.  Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype , 2015, Proceedings of the National Academy of Sciences.

[10]  D. Brenner,et al.  Evidence for a common progenitor of epithelial and mesenchymal components of the liver , 2013, Cell Death and Differentiation.

[11]  Walter de Back,et al.  Transdifferentiation of pancreatic cells by loss of contact-mediated signaling , 2013, BMC Systems Biology.

[12]  Eshel Ben-Jacob,et al.  The three-way switch operation of Rac1/RhoA GTPase-based circuit controlling amoeboid-hybrid-mesenchymal transition , 2014, Scientific Reports.

[13]  S. Rafii,et al.  Endothelial Cells Provide a Notch-Dependent Pro-Tumoral Niche for Enhancing Breast Cancer Survival, Stemness and Pro-Metastatic Properties , 2014, PloS one.

[14]  M. Ibañes,et al.  Lateral inhibition and neurogenesis: novel aspects in motion. , 2013, International Journal of Developmental Biology.

[15]  Jiri Bartek,et al.  Analysis of Epithelial and Mesenchymal Markers in Ovarian Cancer Reveals Phenotypic Heterogeneity and Plasticity , 2011, PloS one.

[16]  I. Malanchi,et al.  The EMT universe: space between cancer cell dissemination and metastasis initiation. , 2014, Critical reviews in oncogenesis.

[17]  Diana M Vallejo,et al.  Targeting Notch signalling by the conserved miR-8/200 microRNA family in development and cancer cells , 2011, The EMBO journal.

[18]  D. Gilmour,et al.  EMT 2.0: shaping epithelia through collective migration. , 2009, Current opinion in genetics & development.

[19]  Amir Bashan,et al.  Network physiology reveals relations between network topology and physiological function , 2012, Nature Communications.

[20]  H. Gerhardt,et al.  Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting , 2010, Nature Cell Biology.

[21]  R. Olmon,et al.  Antenna–load interactions at optical frequencies: impedance matching to quantum systems , 2012, Nanotechnology.

[22]  G. Weinmaster,et al.  The many facets of Notch ligands , 2008, Oncogene.

[23]  Pamela A. Hoodless,et al.  Slug is a direct Notch target required for initiation of cardiac cushion cellularization , 2008, The Journal of cell biology.

[24]  Adam C. Miller,et al.  cis-Inhibition of Notch by Endogenous Delta Biases the Outcome of Lateral Inhibition , 2009, Current Biology.

[25]  E. Ben-Jacob,et al.  Tristability in cancer-associated microRNA-TF chimera toggle switch. , 2013, The journal of physical chemistry. B.

[26]  Q. Nie,et al.  Nonlinear Growth Kinetics of Breast Cancer Stem Cells: Implications for Cancer Stem Cell Targeted Therapy , 2013, Scientific Reports.

[27]  D. Ish-Horowicz,et al.  Periodic Lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to notch signaling. , 2002, Developmental cell.

[28]  Wen Shi,et al.  Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. , 2007, Cancer research.

[29]  K. Salaita,et al.  Membrane tethered delta activates notch and reveals a role for spatio-mechanical regulation of the signaling pathway. , 2013, Biophysical journal.

[30]  M. Ibañes,et al.  Ligand-dependent Notch signaling strength orchestrates lateral induction and lateral inhibition in the developing inner ear , 2014, Development.

[31]  I. Screpanti,et al.  Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. , 2009, Blood.

[32]  Kai-Fai Lee,et al.  MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells. , 2010, Carcinogenesis.

[33]  L. Ellis,et al.  Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. , 2013, Cancer cell.

[34]  N. Park,et al.  TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells. , 2012, Biochemical and biophysical research communications.

[35]  Yibin Kang,et al.  Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. , 2011, Cancer cell.

[36]  A. Oudenaarden,et al.  Cellular Decision Making and Biological Noise: From Microbes to Mammals , 2011, Cell.

[37]  J. Hsieh,et al.  A secreted Delta1‐Fc fusion protein functions both as an activator and inhibitor of Notch1 signaling , 2002, Journal of neuroscience research.

[38]  G. Weinmaster,et al.  Notch ligand endocytosis: mechanistic basis of signaling activity. , 2012, Seminars in cell & developmental biology.

[39]  L. Liaw,et al.  Soluble forms of the Notch ligands Delta1 and Jagged1 promote in vivo tumorigenicity in NIH3T3 fibroblasts with distinct phenotypes. , 2008, The American journal of pathology.

[40]  Bin Wu,et al.  A multi-phenotypic cancer model with cell plasticity. , 2013, Journal of theoretical biology.

[41]  K. Struhl,et al.  Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion , 2011, Proceedings of the National Academy of Sciences.

[42]  Iva Greenwald,et al.  Reciprocal changes in expression of the receptor lin-12 and its ligand lag-2 prior to commitment in a C. elegans cell fate decision , 1994, Cell.

[43]  Rickard Sandberg,et al.  Notch signaling: simplicity in design, versatility in function , 2011, Development.

[44]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[45]  Sridhar Ramaswamy,et al.  Circulating Breast Tumor Cells Exhibit Dynamic Changes in Epithelial and Mesenchymal Composition , 2013, Science.

[46]  Xiling Shen,et al.  A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. , 2013, Cell stem cell.

[47]  Mingyao Liu,et al.  Antitumor Action of a Novel Histone Deacetylase Inhibitor, YF479, in Breast Cancer , 2014, Neoplasia.

[48]  Giuseppe Basso,et al.  MiR-34a Targeting of Notch Ligand Delta-Like 1 Impairs CD15+/CD133+ Tumor-Propagating Cells and Supports Neural Differentiation in Medulloblastoma , 2011, PloS one.

[49]  U. Lendahl,et al.  Notch signaling mediates hypoxia-induced tumor cell migration and invasion , 2008, Proceedings of the National Academy of Sciences.

[50]  Eshel Ben-Jacob,et al.  Toward decoding the principles of cancer metastasis circuits. , 2014, Cancer research.

[51]  M. Nieto.  Epithelial Plasticity: A Common Theme in Embryonic and Cancer Cells , 2013, Science.

[52]  A. Harris,et al.  New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. , 2010, Blood.

[53]  Toshiki Saito,et al.  Manic Fringe and Lunatic Fringe Modify Different Sites of the Notch2 Extracellular Region, Resulting in Different Signaling Modulation* , 2001, The Journal of Biological Chemistry.

[54]  C. Perou,et al.  Lunatic fringe deficiency cooperates with the Met/Caveolin gene amplicon to induce basal-like breast cancer. , 2012, Cancer cell.

[55]  K. Pantel,et al.  Plasticity of disseminating cancer cells in patients with epithelial malignancies , 2012, Cancer and Metastasis Reviews.

[56]  A. Puisieux,et al.  Generation of Breast Cancer Stem Cells through Epithelial-Mesenchymal Transition , 2008, PloS one.

[57]  Guanming Wu,et al.  Tumor-suppressive activity of Lunatic Fringe in prostate through differential modulation of Notch receptor activation. , 2014, Neoplasia.

[58]  K. Mostov,et al.  Slug is required for cell survival during partial epithelial-mesenchymal transition of HGF-induced tubulogenesis. , 2007, Molecular biology of the cell.

[59]  Sridhar Ramaswamy,et al.  Circulating Tumor Cell Clusters Are Oligoclonal Precursors of Breast Cancer Metastasis , 2014, Cell.

[60]  A. M. Arias,et al.  A Role of Receptor Notch in Ligand cis-Inhibition in Drosophila , 2010, Current Biology.

[61]  Ming Li,et al.  The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. , 2013, Neoplasia.

[62]  F. DiMeco,et al.  Endothelial cells create a stem cell niche in glioblastoma by providing NOTCH ligands that nurture self-renewal of cancer stem-like cells. , 2011, Cancer research.

[63]  Eshel Ben-Jacob,et al.  Towards elucidating the connection between epithelial–mesenchymal transitions and stemness , 2014, Journal of The Royal Society Interface.

[64]  M. Mattson,et al.  Involvement of Notch Signaling in Wound Healing , 2007, PloS one.

[65]  I. Bernstein,et al.  Jagged2 acts as a Delta-like Notch ligand during early hematopoietic cell fate decisions. , 2011, Blood.

[66]  Michael M. Wang.  Notch signaling and Notch signaling modifiers. , 2011, The international journal of biochemistry & cell biology.

[67]  K. Irvine,et al.  Fringe modulates Notch–ligand interactions , 1997, Nature.

[68]  M. Elowitz,et al.  Cis Interactions between Notch and Delta Generate Mutually Exclusive Signaling States , 2010, Nature.

[69]  Robert Clewley,et al.  Hybrid Models and Biological Model Reduction with PyDSTool , 2012, PLoS Comput. Biol..

[70]  A. Harris,et al.  The Notch Ligand Jagged1 as a Target for Anti-Tumor Therapy , 2014, Front. Oncol..

[71]  R. Hipskind,et al.  Erk5 controls Slug expression and keratinocyte activation during wound healing. , 2008, Molecular biology of the cell.

[72]  Nikolas Nikolaou,et al.  Lunatic fringe promotes the lateral inhibition of neurogenesis , 2009, Development.

[73]  T. Dang,et al.  Manic fringe inhibits tumor growth by suppressing Notch3 degradation in lung cancer. , 2013, American journal of cancer research.

[74]  Eshel Ben-Jacob,et al.  MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination , 2013, Proceedings of the National Academy of Sciences.

[75]  Naama Barkai,et al.  Error Minimization in Lateral Inhibition Circuits , 2010, Science Signaling.

[76]  M. Ibañes,et al.  Competition in Notch Signaling with Cis Enriches Cell Fate Decisions , 2014, PloS one.

[77]  L. Hudson,et al.  Developmental transcription factor slug is required for effective re‐epithelialization by adult keratinocytes , 2005, Journal of cellular physiology.

[78]  J A Sherratt,et al.  Lateral induction by juxtacrine signaling is a new mechanism for pattern formation. , 2000, Developmental biology.

[79]  R. Weinberg,et al.  Tackling the cancer stem cells — what challenges do they pose? , 2014, Nature Reviews Drug Discovery.

[80]  J. Inoue,et al.  NF-κB non-cell-autonomously regulates cancer stem cell populations in the basal-like breast cancer subtype , 2013, Nature Communications.

[81]  David Sprinzak,et al.  Mutual Inactivation of Notch Receptors and Ligands Facilitates Developmental Patterning , 2011, PLoS Comput. Biol..

[82]  Julianne D. Halley,et al.  A General Model for Binary Cell Fate Decision Gene Circuits with Degeneracy: Indeterminacy and Switch Behavior in the Absence of Cooperativity , 2011, PloS one.

[83]  J. Epstein,et al.  Notch Activation of Jagged1 Contributes to the Assembly of the Arterial Wall , 2012, Circulation.

[84]  Marcus Fruttiger,et al.  The Notch Ligands Dll4 and Jagged1 Have Opposing Effects on Angiogenesis , 2009, Cell.

[85]  Plamen Ch. Ivanov,et al.  Network Physiology: Mapping Interactions Between Networks of Physiologic Networks , 2014 .

[86]  M. Kohandel,et al.  Investigating the link between epithelial-mesenchymal transition and the cancer stem cell phenotype: A mathematical approach. , 2010, Journal of theoretical biology.

[87]  Eshel Ben-Jacob,et al.  The physics of bacterial decision making , 2014, Front. Cell. Infect. Microbiol..

[88]  M. Hellström,et al.  Notch as a hub for signaling in angiogenesis. , 2013, Experimental cell research.

[89]  R. Solé,et al.  Why are cellular switches Boolean? General conditions for multistable genetic circuits. , 2009, Journal of theoretical biology.

[90]  Joseph M. Mahaffy,et al.  An Expanded Notch-Delta Model Exhibiting Long-Range Patterning and Incorporating MicroRNA Regulation , 2014, PLoS Comput. Biol..

[91]  Michael B Elowitz,et al.  Fringe proteins modulate Notch-ligand cis and trans interactions to specify signaling states , 2014, eLife.

[92]  J. Massagué,et al.  Cancer Metastasis: Building a Framework , 2006, Cell.

[93]  W. Dalton,et al.  Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. , 2008, Blood.

[94]  G. Weinmaster,et al.  Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2 , 2000, Nature Cell Biology.

[95]  D. Sprinzak,et al.  From Notch signaling to fine-grained patterning: Modeling meets experiments. , 2011, Current opinion in genetics & development.

[96]  P. Maini,et al.  Pattern formation by lateral inhibition with feedback: a mathematical model of delta-notch intercellular signalling. , 1996, Journal of theoretical biology.

[97]  T. Reh,et al.  Notch signaling specifies prosensory domains via lateral induction in the developing mammalian inner ear , 2010, Proceedings of the National Academy of Sciences.

[98]  Marco Beccuti,et al.  A Mathematical-Biological Joint Effort to Investigate the Tumor-Initiating Ability of Cancer Stem Cells , 2014, PloS one.

[99]  E. Ben-Jacob,et al.  Bacterial survival strategies suggest rethinking cancer cooperativity. , 2012, Trends in microbiology.

[100]  Lutz Brusch,et al.  On the role of lateral stabilization during early patterning in the pancreas , 2013, Journal of The Royal Society Interface.

[101]  Frank McCormick,et al.  Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation. , 2004, Genes & development.

[102]  Julian Lewis,et al.  From Signals to Patterns: Space, Time, and Mathematics in Developmental Biology , 2008, Science.