Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning

Shaya, O.; Binshtok, Udi; Hersch, Micha; Rivkin, Dmitri; Weinreb, Sheila; Amir-Zilberstein, Liat; Khamaisi, Bassma; Oppenheim, Olya; Desai, Ravi A.; Goodyear, Richard J.; Richardson, Guy P.; Chen, Christopher; Sprinzak, David

doi:10.1016/j.devcel.2017.02.009

Cited by 160 publications

(189 citation statements)

References 36 publications

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“…Interestingly, we noted smaller cells to be more likely to differentiate, which is consistent with previous experimental observations showing that Notch signalling is dependent on cell-cell contact area and that hair-cell precursors in the inner ear tend to be smaller (Shaya et al, 2017). We further evaluated the effect of the growth rate and observed that in fast-growing tissues, Notch activity becomes more homogeneous and fewer cells have low Notch activity.…”

Section: Discussionsupporting

confidence: 90%

“…We also observed that cells with low Notch signal, and consequently high levels of Delta, tend to be smaller (Figure 1a,c). This is consistent with experimental observations showing that the cell contact area affects Notch signalling and that smaller cells are more likely to differentiate, as observed in hair cell precursors in the inner ear (Shaya et al, 2017).…”

Section: Effect Of Asymmetry In Cell Division On Notch-mediated Cell supporting

confidence: 92%

“…This can lead to dynamic changes in cell morphology, such as cell shape, contact area, and cell neighbours. Notch signalling activity has been shown to be highly dependent on cell morphological properties such as cell-cell adhesion (Hatakeyama et al, 2014), cell-cell contact area (Shaya et al, 2017), and asymmetry in cell division (Kosodo et al, 2004). Here, to facilitate the study of the effect of cell morphology and neighbour relationships on Notch activity, we established a 2D cell-based simulation environment to simulate Notch-mediated cell differentiation in a growing epithelial tissue.…”

Section: Introductionmentioning

confidence: 99%

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Cell-based simulations of Notch-dependent cell differentiation on growing domains

Stopka

Boareto

Iber

2019

Preprint

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Notch signalling controls cell differentiation and proliferation in many tissues. The Notch signal is generated by the interaction between the Notch receptor of one cell with the Notch ligand (Delta or Jagged) of a neighbouring cell. Therefore, the pathway requires cell-cell contact in order to be active.During organ development, cell differentiation occurs concurrently with tissue growth and changes in cell morphology. How growth impacts on Notch signalling and cell differentiation remains poorly understood. Here, we developed a modelling environment to simulate Notch signalling in a growing tissue. We use our model to simulate the differentiation process of pancreatic progenitor cells. Our results suggest that Notch-mediated differentiation in the developing pancreas is first mediated by geometric effects that result in loss of Notch signalling on the tissue boundary, leading to the differentiation of tip versus trunk cells. A second wave of differentiation further happens in the trunk cells due to a reduction in the expression of the ligand Jagged, which has been shown to be controlled by signalling factors secreted from the surrounding mesenchyme. Our results bring new insights into how cells coordinate tissue growth with cell fate specification during organ development.

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Section: Discussionsupporting

confidence: 90%

Section: Effect Of Asymmetry In Cell Division On Notch-mediated Cell supporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Cell-based simulations of Notch-dependent cell differentiation on growing domains

Stopka

Boareto

Iber

2019

Preprint

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“…Thus, cochlear cell fate commitment is extremely sensitive to the levels of Notch signaling. In this way, Fringe proteins can influence hair cell specification …”

Section: Grns Related To Notch Signalingmentioning

confidence: 99%

The acquisition of positional information across the radial axis of the cochlea

Munnamalai

Fekete

2019

Developmental Dynamics

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The mammalian cochlea detects sound and transmits this information to the brain. A cross section through the cochlea reveals functionally distinct epithelial domains arrayed around the circumference of a fluid‐filled duct. Six major domains include two on the roof of the duct (Reissner's membrane medially and the stria vascularis laterally) and four across the floor of the duct, including the medial and lateral halves of the sensory domain, the organ of Corti. These radial domains are distinguishable in the embryonic cochlea by differential expression of transcription factors, and we focus here on a subset of the factors that can influence cochlear fates. We then move upstream of these genes to identify which of five signaling pathways (Notch, Fgf, Wnt, Bmp, and Shh) controls their spatial patterns of expression. We link the signaling pathways to their downstream genes, separating them by their radial position, to create putative gene regulatory networks (GRNs) from two time points, before and during the time when six radial compartments arise. These GRNs offer a framework for understanding the acquisition of positional information across the radial axis of the cochlea, and to guide therapeutic approaches to repair or regenerate distinct cochlear components that may contribute to hearing loss.

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“…The exchange of Jagged ligands that bind through the Notch receptor facilitates bi-directional cross-talk between cells, stabilizes hybrid E/M cell phenotype(s) and promotes resistance to therapies (55)(56)(57). Previous efforts to couple EMT with intercellular signaling have disregarded the loss of cell-cell adhesion leading to a reduced cell-to-cell signaling between mesenchymal cells (58). Also, we recently showed that JAG1, a Jagged ligand subtype, promotes the growth of tumor organoids in breast cancer cells in vitro (12).…”

Section: What Molecular Mechanisms Can Maximize the Metastatic Potentmentioning

confidence: 99%

A biophysical model of Epithelial-Mesenchymal Transition uncovers the frequency and size distribution of Circulating Tumor Cell clusters across cancer types

Bocci

2019

Preprint

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The gain of cellular motility via the epithelial-mesenchymal transition (EMT) is considered crucial in the metastatic cascade. Cells undergoing EMT to varying extents are launched into the bloodstream as single circulating tumor cells (CTCs) or multi-cellular clusters. The frequency and size distributions of these multicellular clusters has been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood. We present a biophysical model that couples the epithelialmesenchymal phenotypic transition and cell migration to explain these different modes of cancer cell migration. With this reduced physical model, we identify a transition from individual migration to clustered cell migration that is regulated by the rate of EMT and the degree of cooperativity between cells during migration. This single cell to clustered migration transition can robustly recapitulate cluster size distributions observed experimentally across several cancer types, thus suggesting the existence of common features in the mechanisms of cell migration during metastasis. Furthermore, we identify three main mechanisms that can facilitate the formation and dissemination of large clusters: first, mechanisms that prevent a complete EMT and instead increase the population of hybrid Epithelial/Mesenchymal (E/M) cells; second, multiple intermediate E/M states that give rise to heterogeneous clusters formed by cells with different epithelial-mesenchymal traits; and third, non-cell-autonomous induction of EMT via cell-tocell signaling that gives rise to spatial correlations among cells in a tissue. Overall, this biophysical model represents a first step toward bridging the gap between the molecular and biophysical understanding of EMT and various modes of cancer cell migration, and highlights that a complete EMT might not be required for metastasis. Statement of significanceThe Epithelial-Mesenchymal Transition (EMT) confers motility and invasive traits to cancer cells. These cells can then enter the circulatory system both as single cells or as multi-cellular clusters to initiate metastases.We develop a biophysical model to investigate how EMT at the single cell level can give rise to a solitary or clustered cell migration. This model quantitatively reproduces cluster size distributions reported in human circulation and mouse models, therefore suggesting similar mechanisms in cancer cell migration across different cancer types. Moreover, we show that a partial EMT to a hybrid epithelial/mesenchymal cell state is sufficient to explain both single cell and clustered migration, therefore questioning the necessity of a complete EMT for cancer metastasis.

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Cell-Cell Contact Area Affects Notch Signaling and Notch-Dependent Patterning

Cited by 160 publications

References 36 publications

Cell-based simulations of Notch-dependent cell differentiation on growing domains

Cell-based simulations of Notch-dependent cell differentiation on growing domains

The acquisition of positional information across the radial axis of the cochlea

A biophysical model of Epithelial-Mesenchymal Transition uncovers the frequency and size distribution of Circulating Tumor Cell clusters across cancer types

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