scholarly journals Systems biology approach suggests new miRNAs as phenotypic stability factors in the epithelial–mesenchymal transition

2020 ◽  
Vol 17 (171) ◽  
pp. 20200693
Author(s):  
Daner A. Silveira ◽  
Shantanu Gupta ◽  
José Carlos M. Mombach
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Dose Dependence ◽  
Stability Factor ◽  
Phenotypic Stability ◽  
Mesenchymal Transition ◽  
Hybrid State ◽  
Breast Cells ◽  
Mcf10a Cells ◽  
Phenotypic Transition ◽  
Autocrine Mechanism

The epithelial–mesenchymal transition (EMT) is a cellular programme on which epithelial cells undergo a phenotypic transition to mesenchymal ones acquiring metastatic properties such as mobility and invasion. TGF-β signalling can promote the EMT process. However, the dynamics of the concentration response of TGF-β-induced EMT is not well explained. In this work, we propose a logical model of TGF-β dose dependence of EMT in MCF10A breast cells. The model outcomes agree with experimentally observed phenotypes for the wild-type and perturbed/mutated cases. As important findings of the model, it predicts the coexistence of more than one hybrid state and that the circuit between TWIST1 and miR-129 is involved in their stabilization. Thus, miR-129 should be considered as a phenotypic stability factor. The circuit TWIST1/miR-129 associates with ZEB1-mediated circuits involving miRNAs 200, 1199, 340, and the protein GRHL2 to stabilize the hybrid state. Additionally, we found a possible new autocrine mechanism composed of the circuit involving TGF-β, miR-200, and SNAIL1 that contributes to the stabilization of the mesenchymal state. Therefore, our work can extend our comprehension of TGF-β-induced EMT in MCF10A cells to potentially improve the strategies for breast cancer treatment.

scholarly journals NRF2-dependent epigenetic regulation can promote the hybrid epithelial/mesenchymal phenotype

2021 ◽  
Author(s):  
Wen Jia ◽  
Mohit Kumar Jolly ◽  
Herbert Levine
Keyword(s):  
Epigenetic Regulation ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Factor ◽  
Epigenetic Inheritance ◽  
Stability Factor ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Hybrid State ◽  
Regulation Model

AbstractThe epithelial-mesenchymal transition (EMT) is a cellular process critical for wound healing, cancer metastasis and embryonic development. Recent efforts have identified the role of hybrid epithelial/mesenchymal states, having both epithelial and mesehncymal traits, in enabling cancer metastasis and resistance to various therapies. Also, previous work has suggested that NRF2 can act as phenotypic stability factor to help stablize such hybrid states. Here, we incorporate a phenomenological epigenetic feedback effect into our previous computational model for EMT signaling. We show that this type of feedback can stabilize the hybrid state as compared to the fully mesenchymal phenotype if NRF2 can influence SNAIL at an epigenetic level, as this link makes transitions out of hybrid state more difficult. However, epigenetic regulation on other NRF2-related links do not significantly change the EMT dynamics. Finally, we considered possible cell division effects in our epigenetic regulation model, and our results indicate that the degree of epigenetic inheritance does not appear to be a critical factor for the hybrid E/M state stabilizing behavior of NRF2.

scholarly journals Nrf2 regulates collective cancer migration by modulating the hybrid epithelial/mesenchymal phenotype

2021 ◽  
Author(s):  
Samuel A Vilchez Mercedes ◽  
Federico Bocci ◽  
Ninghao Zhu ◽  
Herbert Levine ◽  
José N Onuchic ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Leading Edge ◽  
Stability Factor ◽  
Phenotypic Stability ◽  
Interior Region ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Cancer Migration ◽  
Aggressive Cancer

AbstractHybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. A challenge is to understand how these cells, which are mostly non-existent in healthy tissue, become stable phenotypes participating collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process. Here, using a combined experimental-computational approach, we show that Nrf2 functions as a phenotypic stability factor for hybrid E/M cells by inhibiting a complete epithelial-mesenchymal transition (EMT) during collective cancer migration. We demonstrate that Nrf2 and EMT signaling are spatially coordinated near the migrating front. Computational analysis of Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment and CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype maximally observed in the interior region immediately behind the leading edge. We further demonstrate that the Nrf2-EMT-Notch network enhances Dll4 and Jagged1 expression near the leading edge, which correlates with the formation of protruding tips and leader cells. Together, Nrf2 acts as a phenotypic stability factor in restricting complete EMT and coordinating collective cancer migration.

scholarly journals NFATc acts as a non-canonical phenotypic stability factor for a hybrid epithelial/mesenchymal phenotype

2020 ◽  
Author(s):  
Ayalur Raghu Subbalakshmi ◽  
Deepali Kundnani ◽  
Kuheli Biswas ◽  
Anandamohan Ghosh ◽  
Samir M Hanash ◽  
...  
Keyword(s):  
Phenotypic Plasticity ◽  
Regulatory Networks ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Stochastic Simulations ◽  
Stability Factor ◽  
Dependent Manner ◽  
Phenotypic Stability ◽  
Mesenchymal Transition ◽  
Reversible Transitions

AbstractMetastasis remains the cause of over 90% of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes - Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-Epithelial Transition (MET) - form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor NFATc can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the co-existence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or context-dependent manner. Together, our results indicate that NFATc behaves as a non-canonical phenotypic stability factor for a hybrid E/M phenotype.

scholarly journals Modeling a gene regulatory network of EMT hybrid states for mouse embryonic skin cells

2019 ◽  
Author(s):  
Dan Ramirez ◽  
Vivek Kohar ◽  
Ataur Katebi ◽  
Mingyang Lu
Keyword(s):  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Epithelial Mesenchymal Transition ◽  
Expression Patterns ◽  
Mesenchymal Transition ◽  
Hybrid State ◽  
Regulatory Interactions ◽  
Skin Cells ◽  
Embryonic Skin ◽  
Gene Regulatory

AbstractEpithelial-mesenchymal transition (EMT) plays a crucial role in embryonic development and tumorigenesis. Although EMT has been extensively studied with both computational and experimental methods, the gene regulatory mechanisms governing the transition are not yet well understood. Recent investigations have begun to better characterize the complex phenotypic plasticity underlying EMT using a computational systems biology approach. Here, we analyzed recently published single-cell RNA sequencing data from E9.5 to E11.5 mouse embryonic skin cells and identified the gene expression patterns of both epithelial and mesenchymal phenotypes, as well as a clear hybrid state. By integrating the scRNA-seq data and gene regulatory interactions from the literature, we constructed a gene regulatory network model governing the decision-making of EMT in the context of the developing mouse embryo. We simulated the network using a recently developed mathematical modeling method, named RACIPE, and observed three distinct phenotypic states whose gene expression patterns can be associated with the epithelial, hybrid, and mesenchymal states in the scRNA-seq data. Additionally, the model is in agreement with published results on the composition of EMT phenotypes and regulatory networks. We identified Wnt signaling as a major pathway in inducing the EMT and its role in driving cellular state transitions during embryonic development. Our findings demonstrate a new method of identifying and incorporating tissue-specific regulatory interactions into gene regulatory network modeling.Author SummaryEpithelial-mesenchymal transition (EMT) is a cellular process wherein cells become disconnected from their surroundings and acquire the ability to migrate through the body. EMT has been observed in biological contexts including development, wound healing, and cancer, yet the regulatory mechanisms underlying it are not well understood. Of particular interest is a purported hybrid state, in which cells can retain some adhesion to their surroundings but also show mesenchymal traits. Here, we examine the prevalence and composition of the hybrid state in the context of the embryonic mouse, integrating gene regulatory interactions from published experimental results as well as from the specific single cell RNA sequencing dataset of interest. Using mathematical modeling, we simulated a regulatory network based on these sources and aligned the simulated phenotypes with those in the data. We identified a hybrid EMT phenotype and revealed the inducing effect of Wnt signaling on EMT in this context. Our regulatory network construction process can be applied beyond EMT to illuminate the behavior of any biological phenomenon occurring in a specific context, allowing better identification of therapeutic targets and further research directions.

Rosehip Oil Promotes Excisional Wound Healing by Accelerating the Phenotypic Transition of Macrophages

Planta Medica ◽  
2018 ◽  
Vol 85 (07) ◽  
pp. 563-569 ◽  
Author(s):  
Zhiyong Lei ◽  
Zhijian Cao ◽  
Zaiwang Yang ◽  
Mingzhang Ao ◽  
Wenwen Jin ◽  
...  
Keyword(s):  
Wound Healing ◽  
Epithelial Mesenchymal Transition ◽  
New Drugs ◽  
Mesenchymal Transition ◽  
Excisional Wound ◽  
Macrophage Phenotypes ◽  
Immunohistological Staining ◽  
Underlying Mechanisms ◽  
Global Threat ◽  
Phenotypic Transition

AbstractPoor wound healing is a major and global threat to public health. Efforts have been made to better understand the underlying mechanisms and develop effective remedies, though the advancements that have been made are still limited. As there are no effective and generally applicable therapies available for skin injuries and fibrosis, it is urgent to develop new drugs and therapies that facilitate wound healing and effectively improve scars. In this study, GC-MS analysis was performed to identify the chemical composition of rosehip oil. The excisional wound healing model and the carrageenan-induced paw edema method were respectively applied to evaluate the wound healing activity and anti-inflammatory activity of rosehip oil. Hematoxylin and eosin staining was used to assess the pathological changes of sections, and Sirius-red staining was performed to analyze the ratio of collagen I/III in wound tissues. Immunohistological staining for CD68, CCR7 (CD197), CD163, TGF-β1, and α-SMA was applied to determine the macrophage phenotypes transition (M1-to-M2) and demonstrate the scar-improving efficacy of rosehip oil on wound healing. Results showed that rosehip oil significantly promoted wound healing and effectively improved scars. This efficacy might be exerted by accelerating the macrophage phenotypes transition and inhibiting the process of epithelial-mesenchymal transition.

scholarly journals Suppression of MicroRNA 200 Family Expression by Oncogenic KRAS Activation Promotes Cell Survival and Epithelial-Mesenchymal Transition in KRAS-Driven Cancer

2016 ◽  
Vol 36 (21) ◽  
pp. 2742-2754 ◽  
Author(s):  
Xiaomin Zhong ◽  
Lan Zheng ◽  
Jianfeng Shen ◽  
Dongmei Zhang ◽  
Minmin Xiong ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Protein Translation ◽  
Cellular Transformation ◽  
Tumor Formation ◽  
Regulate Gene Expression ◽  
Mesenchymal Transition ◽  
Pancreatic Cancers ◽  
Mcf10a Cells

Oncogenic KRAS contributes to malignant transformation, antiapoptosis, and metastasis in multiple human cancers, such as lung, colon, and pancreatic cancers and melanoma. MicroRNAs (miRNAs) are endogenous 18- to 25-nucleotide noncoding small RNAs that regulate gene expression in a sequence-specific manner via the degradation of target mRNAs or inhibition of protein translation. In the present study, using array-based miRNA profiling in IMR90 and MCF10A cells expressing oncogenic KRAS, we identified that the expression of the microRNA 200 (mir-200) family was suppressed by KRAS activation and that this suppression was mediated by the transcription factors JUN and SP1 in addition to ZEB1. Restoration of mir-200 expression compromised KRAS-induced cellular transformationin vitroand tumor formationin vivo. In addition, we found that enforced expression of mir-200 abrogated KRAS-induced resistance to apoptosis by directly targeting the antiapoptotic geneBCL2. Finally, mir-200 was able to antagonize the epithelial-mesenchymal transition (EMT) driven by mutant KRAS. Collectively, our results suggest that repression of endogenous mir-200 expression is one of the important cellular responses to KRAS activation during tumor initiation and progression.

scholarly journals Twist1 and Slug mediate H2AX-regulated epithelial-mesenchymal transition in breast cells

Cell Cycle ◽  
2016 ◽  
Vol 15 (18) ◽  
pp. 2398-2404 ◽  
Author(s):  
Urbain Weyemi ◽  
Christophe E. Redon ◽  
Taresh K. Sethi ◽  
Allison S. Burrell ◽  
Parthav Jailwala ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Breast Cells

scholarly journals Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

2018 ◽  
Author(s):  
Mohit Kumar Jolly ◽  
Bogdan-Tiberius Preca ◽  
Satyendra C Tripathi ◽  
Dongya jia ◽  
Samir M Hanash ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Computational Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Feedback Loops ◽  
Carcinoma Cells ◽  
Migration And Invasion ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Mcf10a Cells ◽  
Stable Hybrid

AbstractAberrant activation of epithelial-mesenchymal transition (EMT) in carcinoma cells contributes to increased migration and invasion, metastasis, drug resistance, and tumor-initiating capacity. EMT is not always a binary process, rather cells may exhibit a hybrid epithelial/mesenchymal (E/M) phenotype. ZEB1 - a key transcription factor driving EMT - can both induce and maintain a mesenchymal phenotype. Recent studies have identified two novel autocrine feedback loops utilizing ESRP1, HAS2, and CD44 that maintain high levels of ZEB1. However, how the crosstalk between these feedback loops alters the dynamics of epithelial-hybrid-mesenchymal transition remains elusive. Here, using an integrated theoretical-experimental framework, we identify that these feedback loops can enable cells to stably maintain a hybrid E/M phenotype. Moreover, computational analysis identifies the regulation of ESRP1 as a crucial node, a prediction that is validated by two complementary experiments showing that (a) overexpression of ESRP1 reverts EMT in MCF10A cells treated with TGFβ for 21 days, and (b) knockdown of ESRP1 in stable hybrid E/M H1975 cells drives EMT. Finally, in multiple breast cancer datasets, high levels of ESRP1, ESRP1/HAS2, and ESRP1/ZEB1 correlates with poor prognosis, supporting the relevance of ZEB1/ESRP1 and ZEB1/HAS2 axes in tumor progression. Together, our results unravel how these interconnected feedback loops act in concert to regulate ZEB1 levels and to drive the dynamics of epithelial-hybrid-mesenchymal transition.

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

2020 ◽  
Author(s):  
Ayalur Raghu Subbalakshmi ◽  
Sarthak Sahoo ◽  
Kuheli Biswas ◽  
Mohit Kumar Jolly
Keyword(s):  
Systems Biology ◽  
Epithelial Mesenchymal Transition ◽  
Specific Property ◽  
Therapy Resistance ◽  
Stability Factor ◽  
Computational Systems Biology ◽  
Mesenchymal Transition ◽  
Patient Prognosis ◽  
Metastasis Therapy ◽  
Computational Systems

AbstractEpithelial-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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