Dataset Information

Morphological State Transition Dynamics in EGF-Induced Epithelial to Mesenchymal Transition.

ABSTRACT: Epithelial to Mesenchymal Transition (EMT) is a multi-state process. Here, we investigated phenotypic state transition dynamics of Epidermal Growth Factor (EGF)-induced EMT in a breast cancer cell line MDA-MB-468. We have defined phenotypic states of these cells in terms of their morphologies and have shown that these cells have three distinct morphological states-cobble, spindle, and circular. The spindle and circular states are the migratory phenotypes. Using quantitative image analysis and mathematical modeling, we have deciphered state transition trajectories in different experimental conditions. This analysis shows that the phenotypic state transition during EGF-induced EMT in these cells is reversible, and depends upon the dose of EGF and level of phosphorylation of the EGF receptor (EGFR). The dominant reversible state transition trajectory in this system was cobble to circular to spindle to cobble. We have observed that there exists an ultrasensitive on/off switch involving phospho-EGFR that decides the transition of cells in and out of the circular state. In general, our observations can be explained by the conventional quasi-potential landscape model for phenotypic state transition. As an alternative to this model, we have proposed a simpler discretized energy-level model to explain the observed state transition dynamics.

SUBMITTER: Devaraj V

PROVIDER: S-EPMC6678216 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Morphological State Transition Dynamics in EGF-Induced Epithelial to Mesenchymal Transition.

Devaraj Vimalathithan V Bose Biplab B

Journal of clinical medicine 20190626 7

Epithelial to Mesenchymal Transition (EMT) is a multi-state process. Here, we investigated phenotypic state transition dynamics of Epidermal Growth Factor (EGF)-induced EMT in a breast cancer cell line MDA-MB-468. We have defined phenotypic states of these cells in terms of their morphologies and have shown that these cells have three distinct morphological states-cobble, spindle, and circular. The spindle and circular states are the migratory phenotypes. Using quantitative image analysis and ma ...[more]

PMID: 31247884

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Project description:BACKGROUND: The microenvironment plays a pivotal role in tumor cell proliferation, survival and migration. Invasive cancer cells face a new set of environmental challenges as they breach the basement membrane and colonize distant organs during the process of metastasis. Phenotypic switching, such as that which occurs during epithelial-mesenchymal transition (EMT), may be associated with a remodeling of cell surface receptors and thus altered responses to signals from the tumor microenvironment. METHODOLOGY/PRINCIPAL FINDINGS: We assessed changes in intracellular Ca(2+) in cells loaded with Fluo-4 AM using a fluorometric imaging plate reader (FLIPR(TETRA)) and observed significant changes in the potency of ATP (EC(50) 0.175 µM (-EGF) versus 1.731 µM (+EGF), P<0.05), and the nature of the ATP-induced Ca(2+) transient, corresponding with a 10-fold increase in the mesenchymal marker vimentin (P<0.05). We observed no change in the sensitivity to PAR2-mediated Ca(2+) signaling, indicating that these alterations are not simply a consequence of changes in global Ca(2+) homeostasis. To determine whether changes in ATP-mediated Ca(2+) signaling are preceded by alterations in the transcriptional profile of purinergic receptors, we analyzed the expression of a panel of P2X ionotropic and P2Y metabotropic purinergic receptors using real-time RT-PCR and found significant and specific alterations in the suite of ATP-activated purinergic receptors during EGF-induced EMT in breast cancer cells. Our studies are the first to show that P2X(5) ionotropic receptors are enriched in the mesenchymal phenotype and that silencing of P2X(5) leads to a significant reduction (25%, P<0.05) in EGF-induced vimentin protein expression. CONCLUSIONS: The acquisition of a new suite of cell surface purinergic receptors is a feature of EGF-mediated EMT in MDA-MB-468 breast cancer cells. Such changes may impart advantageous phenotypic traits and represent a novel mechanism for the targeting of cancer metastasis.

Dataset Information

Morphological State Transition Dynamics in EGF-Induced Epithelial to Mesenchymal Transition.

Publications

Morphological State Transition Dynamics in EGF-Induced Epithelial to Mesenchymal Transition.

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