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Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling.

ABSTRACT: Epithelial cell plasticity, a hallmark of carcinoma progression, results in local and distant cancer dissemination. Carcinoma cell plasticity can be achieved through epithelial-mesenchymal transition (EMT), with cells positioned seemingly indiscriminately across the spectrum of EMT phenotypes. Different degrees of plasticity are achieved by transcriptional regulation and feedback-loops, which confer carcinoma cells with unique properties of tumor propagation and therapy resistance. Decoding the molecular and cellular basis of EMT in carcinoma should enable the discovery of new therapeutic strategies against cancer. In this review, we discuss the different attributes of plasticity in carcinoma and highlight the role of the canonical TGFβ receptor signaling pathway in the acquisition of plasticity. We emphasize the potential stochasticity of stemness in carcinoma in relation to plasticity and provide data from recent clinical trials that seek to target plasticity.

SUBMITTER: Wang X

PROVIDER: S-EPMC8307280 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling.

Wang Xuecong X Thiery Jean Paul JP

Cancers 20210707 14

Epithelial cell plasticity, a hallmark of carcinoma progression, results in local and distant cancer dissemination. Carcinoma cell plasticity can be achieved through epithelial-mesenchymal transition (EMT), with cells positioned seemingly indiscriminately across the spectrum of EMT phenotypes. Different degrees of plasticity are achieved by transcriptional regulation and feedback-loops, which confer carcinoma cells with unique properties of tumor propagation and therapy resistance. Decoding the ...[more]

PMID: 34298613

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Project description:BackgroundThe family of TGF-? ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGF-? ligands eliciting both sustained or transient responses. Members of the TGF-? family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. A number of different models have been proposed to reconcile these different behaviours. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGF-? signaling network.ResultsTo define the key aspects for signaling plasticity we focused on the core of the TGF-? signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The intensity of a constant signal (i.e. the ligand concentration), on the other hand, affected only the strength but not the type of the response.ConclusionsThe architecture of the TGF-? pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGF-? ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways. It will be interesting to uncover the exact cellular differences as well as the details of the cross-talks in future work.

Dataset Information

Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling.

Publications

Harnessing Carcinoma Cell Plasticity Mediated by TGF-β Signaling.

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