Toward Decoding the Principles of Cancer Metastasis Circuits

Lu, Mingyang; Jolly, Mohit Kumar; Onuchic, José N.; Ben‐Jacob, Eshel

doi:10.1158/0008-5472.can-13-3367

Cited by 54 publications

(53 citation statements)

References 102 publications

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“…We expect that this hybrid state plays an absolutely critical role in mediating communication between cells that have undergone partial EMT and move collectively (28,55,56). Notch signaling observed during wound healing (57), a typical case of partial EMT, supports this hypothesis.…”

Section: Discussionmentioning

confidence: 69%

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

Boareto

Jolly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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141

226

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Notch signaling pathway mediates cell-fate determination during embryonic development, wound healing, and tumorigenesis. This pathway is activated when the ligand Delta or the ligand Jagged of one cell interacts with the Notch receptor of its neighboring cell, releasing the Notch Intracellular Domain (NICD) that activates many downstream target genes. NICD affects ligand production asymmetrically––it represses Delta, but activates Jagged. Although the dynamical role of Notch–Jagged signaling remains elusive, it is widely recognized that Notch–Delta signaling behaves as an intercellular toggle switch, giving rise to two distinct fates that neighboring cells adopt––Sender (high ligand, low receptor) and Receiver (low ligand, high receptor). Here, we devise a specific theoretical framework that incorporates both Delta and Jagged in Notch signaling circuit to explore the functional role of Jagged in cell-fate determination. We find that the asymmetric effect of NICD renders the circuit to behave as a three-way switch, giving rise to an additional state––a hybrid Sender/Receiver (medium ligand, medium receptor). This phenotype allows neighboring cells to both send and receive signals, thereby attaining similar fates. We also show that due to the asymmetric effect of the glycosyltransferase Fringe, different outcomes are generated depending on which ligand is dominant: Delta-mediated signaling drives neighboring cells to have an opposite fate; Jagged-mediated signaling drives the cell to maintain a similar fate to that of its neighbor. We elucidate the role of Jagged in cell-fate determination and discuss its possible implications in understanding tumor–stroma cross-talk, which frequently entails Notch–Jagged communication.

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Section: Discussionmentioning

confidence: 69%

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

Boareto

Jolly

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

141

226

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“…Because EMT is no longer considered to be a binary process [6,57,58], and stemness is being understood as a reversible trait of cells rather than their fixed state [59], such multistability, as also observed during transitions between amoeboid and mesenchymal phenotypes [60], might be used by cancer cells to adapt to their changing microenvironments.…”

Section: Discussionmentioning

confidence: 99%

Towards elucidating the connection between epithelial–mesenchymal transitions and stemness

Jolly

Huang

et al. 2014

J. R. Soc. Interface.

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178

166

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Epithelial cells undergoing epithelial-to-mesenchymal transitions have often been shown to behave as cancer stem cells, but the precise molecular connection remains elusive. At the genetic level, stemness is governed by LIN28/let-7 double inhibition switch, whereas EMT/MET is controlled by miR-200/ZEB double inhibition circuit and LIN28 is inhibited by miR-200, coupling the two modules. Here, using a specially devised theoretical framework to investigate the dynamics of the LIN28/let-7 system, we show that it can operate as a three-way switch (between low, high and intermediate LIN28 levels termed the D, U and hybrid D/U states) similar to the three-way operation of the miR-200/ZEB circuit that allows for the existence of a hybrid epithelial/ mesenchymal (E/M) phenotype. We find significant correspondence between the existence of the three states of the two circuits: E-D, M-U and E/M-D/U. Incorporating the activation of OCT4 by LIN28, we find that the hybrid E/M phenotype has high likelihood (when compared with either the E or M states) to gain stemness. Combining the LIN28/let-7 regulation by NF-kB and c-MYC, we find that NF-kB, but not c-MYC, elevates the likelihood of E/M phenotype to gain stemness. Our results are consistent with emerging concept that partial EMT can lead to stemness.

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“…In this work, we used Hill function to represent all activation and repression regulations for simplicity. As such, the model can be further complemented by considering the detailed miRNA-mediated regulation dynamics (8,50).…”

Section: Discussionmentioning

confidence: 99%

Quantifying the Landscape for Development and Cancer from a Core Cancer Stem Cell Circuit

Wang

2015

Cancer Research

101

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Cancer presents a serious threat to human health. The understanding of the cell fate determination during development and tumor-genesis remains challenging in current cancer biology. It was suggested that cancer stem cell (CSC) may arise from normal stem cells or be transformed from normal differentiated cells. This gives hints on the connection between cancer and development. However, the molecular mechanisms of these cell-type transitions and the CSC formation remain elusive. We quantified landscape, dominant paths, and switching rates between cell types from a core gene regulatory network for cancer and development. Stem cell, CSC, cancer, and normal cell types emerge as basins of attraction on associated landscape. The dominant paths quantify the transition processes among CSC, stem cell, normal cell, and cancer cell attractors. Transition actions of the dominant paths are shown to be closely related to switching rates between cell types, but not always to the barriers in between, because of the presence of the curl flux. During the process of P53 gene activation, landscape topography changes gradually from a CSC attractor to a normal cell attractor. This confirms the roles of P53 of preventing the formation of CSC through suppressing self-renewal and inducing differentiation. By global sensitivity analysis according to landscape topography and action, we identified key regulations determining cell-type switchings and suggested testable predictions. From landscape view, the emergence of the CSCs and the associated switching to other cell types are the results of underlying interactions among cancer and developmental marker genes. This indicates that the cancer and development are intimately connected. This landscape and flux theoretical framework provides a quantitative way to understand the underlying mechanisms of CSC formation and interplay between cancer and development. Cancer Res; 75(13); 2607-18. Ó2015 AACR.

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Toward Decoding the Principles of Cancer Metastasis Circuits

Cited by 54 publications

References 102 publications

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

Jagged–Delta asymmetry in Notch signaling can give rise to a Sender/Receiver hybrid phenotype

Towards elucidating the connection between epithelial–mesenchymal transitions and stemness

Quantifying the Landscape for Development and Cancer from a Core Cancer Stem Cell Circuit

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