Auto-regulation of Slug mediates its activity during epithelial to mesenchymal transition

Kumar, Brijesh; Uppuladinne, Mallikarjunachari; Jani, Vinod; Sonavane, Uddhavesh; Joshi, Rajendra; Bapat, Sharmila A.

doi:10.1016/j.bbagrm.2015.07.006

Cited by 13 publications

(17 citation statements)

References 58 publications

(63 reference statements)

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“…In contrast, in melanoma cell lines, SNAI1 does not activate the transcription of ZEB1 (Wels et al, 2011), thus, we have not included this interaction in our model. SNAI2 (Kumar et al, 2015) and TWIST1 (Casas et al, 2011) directly activate the transcription of Snai2. SNAI2 also directly induces the transcription of ZEB1 (Wels et al, 2011).…”

Section: Key Transcription Factors For Endothelial and Mesenchymal Idmentioning

confidence: 99%

A Computational Model of the Endothelial to Mesenchymal Transition

2020

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Endothelial cells (ECs) form the lining of lymph and blood vessels. Changes in tissue requirements or wounds may cause ECs to behave as tip or stalk cells. Alternatively, they may differentiate into mesenchymal cells (MCs). These processes are known as EC activation and endothelial-to-mesenchymal transition (EndMT), respectively. EndMT, Tip, and Stalk EC behaviors all require SNAI1, SNAI2, and Matrix metallopeptidase (MMP) function. However, only EndMT inhibits the expression of VE-cadherin, PECAM1, and VEGFR2, and also leads to EC detachment. Physiologically, EndMT is involved in heart valve development, while a defective EndMT regulation is involved in the physiopathology of cardiovascular malformations, congenital heart disease, systemic and organ fibrosis, pulmonary arterial hypertension, and atherosclerosis. Therefore, the control of EndMT has many promising potential applications in regenerative medicine. Despite the fact that many molecular components involved in EC activation and EndMT have been characterized, the system-level molecular mechanisms involved in this process have not been elucidated. Toward this end, hereby we present Boolean network model of the molecular involved in the regulation of EC activation and EndMT. The simulated dynamic behavior of our model reaches fixed and cyclic patterns of activation that correspond to the expected EC and MC cell types and behaviors, recovering most of the specific effects of simple gain and loss-of-function mutations as well as the conditions associated with the progression of several diseases. Therefore, our model constitutes a theoretical framework that can be used to generate hypotheses and guide experimental inquiry to comprehend the regulatory mechanisms behind EndMT. Our main findings include that both the extracellular microevironment and the pattern of molecular activity within the cell regulate EndMT. EndMT requires a lack of VEGFA and sufficient oxygen in the extracellular microenvironment as well as no FLI1 and GATA2 activity within the cell. Additionally Tip cells cannot undergo EndMT directly. Furthermore, the specific conditions that are sufficient to trigger EndMT depend on the specific pattern of molecular activation within the cell.

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Section: Key Transcription Factors For Endothelial and Mesenchymal Idmentioning

confidence: 99%

A Computational Model of the Endothelial to Mesenchymal Transition

2020

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“…transcriptional inhibition of SLUG by SNAIL), we varied the strength of repression of the corresponding link, but did not observe any appreciable change in the phase boundaries (Fig 2D, ii; Fig S2D). SLUG is also known to self-activate in certain contexts [Kumar et al, 2015;Zhou et al, 2019]. Thus, we examined the changes in EMP dynamics upon including SLUG self-activation.…”

Section: Slug Can Act As a 'Phenotypic Stability Factor' For A Hybridmentioning

confidence: 99%

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Subbalakshmi

Sahoo

Biswas

et al. 2020

Preprint

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Epithelial-mesenchymal plasticity comprises of reversible transitions among epithelial, hybrid epithelial/mesenchymal (E/M) and mesenchymal phenotypes, and underlies various aspects of aggressive tumor progression such as metastasis, therapy resistance and immune evasion. The process of cells attaining one or more hybrid E/M phenotypes is termed as partial EMT. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either fully epithelial or mesenchymal state. Thus, identifying regulators of hybrid E/M phenotypes is essential to decipher the rheostats of phenotypic plasticity and consequent accelerators of metastasis. Here, using a computational systems biology approach, we demonstrate that SLUG (SNAIL2) – an EMT-inducing transcription factor – can inhibit cells from undergoing a complete EMT and thus stabilizing them in hybrid E/M phenotype(s). It expands the parametric range enabling the existence of a hybrid E/M phenotype, thereby behaving as a phenotypic stability factor (PSF). Our simulations suggest that this specific property of SLUG emerges from the topology of the regulatory network it forms with other key regulators of epithelial-mesenchymal plasticity. Clinical data suggests that SLUG associates with worse patient prognosis across multiple carcinomas. Together, our results indicate that SLUG can stabilize hybrid E/M phenotype(s).

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“…Immunoblotting protocols were followed as previously described 55 . Briefly, cell lysates were prepared in RIPA buffer (50mM Tris -pH 7.4, 150mM NaCl, 2mM EDTA -pH 8.0, 1% NP-40, 0.1% SDS) containing 2mM PMSF and 1X protease inhibitor cocktail (Roche).…”

Section: Immunoblottingmentioning

confidence: 99%

“…A mathematical model to integrate expression data with reported Tcf21, Slug interactions was developed 55,57 . The model formulation for is given as:…”

Section: Model Generationmentioning

confidence: 99%

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Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer

Kamble

et al. 2018

Preprint

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Cellular plasticity and transitional phenotypes add to complexities of cancer metastasis initiated by single cell epithelial to mesenchymal transition or cooperative cell migration (CCM).We identified novel regulatory cross-talks between Tcf21 and Slug in mediating phenotypic and migration plasticity in high-grade serous ovarian adenocarcinoma. Live imaging discerned CCM as being achieved either through rapid cell proliferation or sheet migration. Transitional states were enriched over the rigid epithelial or mesenchymal phenotypes under conditions of environmental stresses. The Tcf21-Slug interplay identified in HGSC tumors through effective stratification of subtypes also contributed to class-switching in response to disease progression or therapy. Our study effectively provides a framework for understanding the relevance of cellular plasticity in situ as a function of two transcription factors.

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Auto-regulation of Slug mediates its activity during epithelial to mesenchymal transition

Cited by 13 publications

References 58 publications

A Computational Model of the Endothelial to Mesenchymal Transition

A Computational Model of the Endothelial to Mesenchymal Transition

A computational systems biology approach identifies SLUG as a mediator of partial Epithelial-Mesenchymal Transition (EMT)

Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer

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