Epithelial-mesenchymal transition and bi- and multi-nucleated trophoblast cell formation in ovine conceptuses during the peri-implantation period

AbstractEpithelial-mesenchymal transition (EMT) and cancer stem cell formation (CSCs) are two fundamental and well-studied processes contributing to cancer metastasis and tumor relapse. Cells can undergo a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype or a complete EMT to attain a mesenchymal one. Similarly, cells can reversibly gain or lose ‘stemness’. This plasticity in cell states is modulated by signaling pathways such as Notch. However, the interconnections among the cell states enabled by EMT, CSCs and Notch signaling remain elusive. Here, we devise a computational model to investigate the coupling among the core decision-making circuits for EMT, CSCs and the Notch pathway. Our model predicts that hybrid E/M cells are most likely to associate with stemness traits and exhibit enhanced Notch-Jagged signaling – a pathway that is implicated in therapeutic resistance. Further, we show that the position of the ‘stemness window’ on the ‘EMT axis’ is varied by altering the coupling strength between EMT and CSC circuits, and/or modulating Notch signaling. Finally, we analyze the gene expression profile of CSCs from several cancer types and observe a heterogeneous distribution along the ‘EMT axis’, suggesting that different subsets of CSCs may exist with varying phenotypes along the epithelial-mesenchymal plasticity axis. Our computational model offers insights into the complex EMT-stemness interplay and provides a platform to investigate the effects of therapeutic perturbations such as treatment with metformin, a common anti-diabetic drug that has been associated with decreased cancer incidence and increased lifespan of patients. Our mechanism-based model helps explain how metformin can both inhibit EMT and blunt the aggressive potential of CSCs simultaneously, by driving the cells out of a hybrid E/M stem-like state with enhanced Notch-Jagged signaling.

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Emodin reduces Breast Cancer Lung Metastasis by suppressing Macrophage-induced Breast Cancer Cell Epithelial-mesenchymal transition and Cancer Stem Cell formation

Theranostics ◽

10.7150/thno.45395 ◽

2020 ◽

Vol 10 (18) ◽

pp. 8365-8381

Author(s):

Qing Liu ◽

Johnie Hodge ◽

Junfeng Wang ◽

Yuzhen Wang ◽

Lianming Wang ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Lung Metastasis ◽

Epithelial Mesenchymal Transition ◽

Cell Formation ◽

Mesenchymal Transition

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Interleukin-27 Inhibits Trophoblast Cell Invasion and Migration by Affecting the Epithelial–Mesenchymal Transition in Preeclampsia

Reproductive Sciences ◽

10.1177/1933719118799206 ◽

2018 ◽

Vol 26 (7) ◽

pp. 928-938 ◽

Cited By ~ 1

Author(s):

Huisheng Ge ◽

Nanlin Yin ◽

Ting-Li Han ◽

Dongni Huang ◽

Xuehai Chen ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Trophoblast Cell ◽

Trophoblast Invasion ◽

Migration And Invasion ◽

Dependent Manner ◽

Signal Transducer ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

Epithelial Phenotype ◽

And Migration

Preeclampsia (PE) is a pregnancy-specific disorder representing a major cause of maternal and perinatal morbidity and mortality. Invasive and migratory phenotypes are acquired by trophoblasts through the process of epithelial–mesenchymal transition (EMT). Studies have shown that trophoblast EMT events are dysregulated in PE and play an important role in its development. Dysregulation of interleukin (IL)-27 and IL-27R (T-cell cytokine receptor (TCCR)/WSX -1) is relevant to PE. In this study, our results demonstrated that IL-27 did not significantly affect the proliferation and apoptosis of HTR -8/SVneo trophoblast cells, while it did significantly inhibit trophoblast invasion and migration. The expression of EMT-related proteins in HTR-8/SVneo cells and extravillous explants was detected after treatment with IL-27. Expression of epithelial markers was increased, and mesenchymal marker expression was reduced. Furthermore, we found that IL-27 could induce significant phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1) and Signal Transducer and Activator of Transcription 3 (STAT3) in a time-dependent manner in HTR-8/SVneo cells. Selective inhibitors of STAT1 (STAT1 siRNA) and STAT3 (STAT3 siRNA) were used to determine whether both STAT1 and STAT3 are required for IL-27-mediated inhibition of EMT. STAT1 inhibition in IL-27-treated cells attenuated the IL-27 effect, while the inhibition of STAT3 activation had no effect on the development of the epithelial phenotype. These results demonstrate that IL-27 may inhibit trophoblast cell migration and invasion by affecting the EMT process through an STAT1-dominant pathway in PE.

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Embryonic trophectoderm secretomics reveals chemotactic migration and intercellular communication of endometrial and circulating MSCs in embryonic implantation

10.21203/rs.3.rs-177701/v1 ◽

2021 ◽

Author(s):

Alexandra Calle ◽

Víctor Toribio-Serrano ◽

María Yáñez-Mó ◽

Miguel Ángel Ramírez

Keyword(s):

Epithelial Mesenchymal Transition ◽

Soluble Fraction ◽

Primary Cultures ◽

Mesenchymal Phenotype ◽

Mesenchymal Transition ◽

Angiogenic Proteins ◽

Uterine Fluid ◽

Related Proteins ◽

Implantation Period

Abstract Embryonic implantation is a key step in the establishment of pregnancy. In the present work, we have carried out an in-depth proteomic analysis of the secretome (extracellular vesicles and soluble proteins) of two bovine blastocysts embryonic trophectoderm primary cultures (BBT), confirming different epithelial-mesenchymal transition stages in these cells. BBT-secretomes contain early pregnancy-related proteins and angiogenic proteins both as cargo in EVs and the soluble fraction. We have demonstrated the functional transfer of protein-containing secretome between embryonic trophectoderm and maternal MSC in vitro using two BBT primary cultures and 8 endometrial MSC (eMSC) and 5 peripheral blood MSC (pbMSC) lines. We observed that eMSC and pbMSC chemotax to both the soluble fraction and EVs of the BBT secretome. In addition, in a complementary direction, we found that the pattern of expression of implantation proteins in BBT-EVs changes depending on: i) their epithelial-mesenchymal phenotype; ii) as a result of the uptake of eMSC- or pbMSC-EVs previously stimulated or not with embryonic signals (IFN-τ), and iii) because of stimulation with endometrial cytokines present in the uterine fluid in the peri-implantation period.

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The Lnc RNA SPRY4-IT1 Modulates Trophoblast Cell Invasion and Migration by Affecting the Epithelial-Mesenchymal Transition

Scientific Reports ◽

10.1038/srep37183 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 37

Author(s):

Qing Zuo ◽

Shiyun Huang ◽

Yanfen Zou ◽

Yetao Xu ◽

Ziyan Jiang ◽

...

Keyword(s):

Cell Invasion ◽

Epithelial Mesenchymal Transition ◽

Trophoblast Cell ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

And Migration

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Updating dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2): molecular basis, functions and role in diseases

Cellular and Molecular Life Sciences ◽

10.1007/s00018-020-03556-1 ◽

2020 ◽

Vol 77 (23) ◽

pp. 4747-4763 ◽

Cited By ~ 1

Author(s):

Alejandro Correa-Sáez ◽

Rafael Jiménez-Izquierdo ◽

Martín Garrido-Rodríguez ◽

Rosario Morrugares ◽

Eduardo Muñoz ◽

...

Keyword(s):

Cell Cycle ◽

Epithelial Mesenchymal Transition ◽

Cell Formation ◽

Tissue Expression ◽

Cancer Development ◽

Patient Response ◽

Mesenchymal Transition ◽

Dual Specificity ◽

Response To Chemotherapy ◽

Cancer Mutations

Abstract Members of the dual-specificity tyrosine-regulated kinase (DYRKs) subfamily possess a distinctive capacity to phosphorylate tyrosine, serine, and threonine residues. Among the DYRK class II members, DYRK2 is considered a unique protein due to its role in disease. According to the post-transcriptional and post-translational modifications, DYRK2 expression greatly differs among human tissues. Regarding its mechanism of action, this kinase performs direct phosphorylation on its substrates or acts as a priming kinase, enabling subsequent substrate phosphorylation by GSK3β. Moreover, DYRK2 acts as a scaffold for the EDVP E3 ligase complex during the G2/M phase of cell cycle. DYRK2 functions such as cell survival, cell development, cell differentiation, proteasome regulation, and microtubules were studied in complete detail in this review. We have also gathered available information from different bioinformatic resources to show DYRK2 interactome, normal and tumoral tissue expression, and recurrent cancer mutations. Then, here we present an innovative approach to clarify DYRK2 functionality and importance. DYRK2 roles in diseases have been studied in detail, highlighting this kinase as a key protein in cancer development. First, DYRK2 regulation of c-Jun, c-Myc, Rpt3, TERT, and katanin p60 reveals the implication of this kinase in cell-cycle-mediated cancer development. Additionally, depletion of this kinase correlated with reduced apoptosis, with consequences on cancer patient response to chemotherapy. Other functions like cancer stem cell formation and epithelial–mesenchymal transition regulation are also controlled by DYRK2. Furthermore, the pharmacological modulation of this protein by different inhibitors (harmine, curcumine, LDN192960, and ID-8) has enabled to clarify DYRK2 functionality.

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