scholarly journals Mechanistic Model of Signaling Dynamics Across an Epithelial Mesenchymal Transition

2020 ◽  
Vol 11 ◽  
Author(s):  
James D. Wade ◽  
Xiao-Kang Lun ◽  
Nevena Zivanovic ◽  
Eberhard O. Voit ◽  
Bernd Bodenmiller
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Network Inference ◽  
Cell Function ◽  
Epithelial Mesenchymal Transition ◽  
Mechanistic Model ◽  
Mesenchymal Transition ◽  
Signaling Dynamics ◽  
Egf Signaling ◽  
Network Rewiring

Intracellular signaling pathways are at the core of cellular information processing. The states of these pathways and their inputs determine signaling dynamics and drive cell function. Within a cancerous tumor, many combinations of cell states and microenvironments can lead to dramatic variations in responses to treatment. Network rewiring has been thought to underlie these context-dependent differences in signaling; however, from a biochemical standpoint, rewiring of signaling networks should not be a prerequisite for heterogeneity in responses to stimuli. Here we address this conundrum by analyzing an in vitro model of the epithelial mesenchymal transition (EMT), a biological program implicated in increased tumor invasiveness, heterogeneity, and drug resistance. We used mass cytometry to measure EGF signaling dynamics in the ERK and AKT signaling pathways before and after induction of EMT in Py2T murine breast cancer cells. Analysis of the data with standard network inference methods suggested EMT-dependent network rewiring. In contrast, use of a modeling approach that adequately accounts for single-cell variation demonstrated that a single reaction-based pathway model with constant structure and near-constant parameters is sufficient to represent differences in EGF signaling across EMT. This result indicates that rewiring of the signaling network is not necessary for heterogeneous responses to a signal and that unifying reaction-based models should be employed for characterization of signaling in heterogeneous environments, such as cancer.

scholarly journals The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 476 ◽  
Author(s):  
Chia-Jung Li ◽  
Pei-Yi Chu ◽  
Giou-Teng Yiang ◽  
Meng-Yu Wu
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Inhibition Of Proliferation ◽  
Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

scholarly journals Carbonic Anhydrase XII Expression Is Modulated during Epithelial Mesenchymal Transition and Regulated through Protein Kinase C Signaling

2020 ◽  
Vol 21 (3) ◽  
pp. 715 ◽  
Author(s):  
Daniele Vergara ◽  
Sara Ravaioli ◽  
Eugenio Fonzi ◽  
Loredaria Adamo ◽  
Marina Damato ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Carbonic Anhydrase ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Epithelial Mesenchymal Transition ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Kinase C ◽  
Pkc Activation

Members of the carbonic anhydrase family are functionally involved in the regulation of intracellular and extracellular pH in physiological and pathological conditions. Their expression is finely regulated to maintain a strict control on cellular homeostasis, and it is dependent on the activation of extracellular and intracellular signaling pathways. Combining RNA sequencing (RNA-seq), NanoString, and bioinformatics data, we demonstrated that the expression of carbonic anhydrase 12 (CAXII) is significantly different in luminal and triple negative breast cancer (BC) models and patients, and is associated with the activation of an epithelial mesenchymal transition (EMT) program. In BC models, the phorbol ester 12-myristate 13-acetate (PMA)-mediated activation of protein kinase C (PKC) induced a down-regulation of CAXII with a concomitant modulation of other members of the transport metabolon, including CAIX and the sodium bicarbonate cotransporter 3 (NBCn1). This is associated with a remodeling of tumor glycolytic metabolism induced after PKC activation. Overall, this analysis highlights the dynamic nature of transport metabolom and identifies signaling pathways finely regulating this plasticity.

scholarly journals Involvement of the ERK/HIF-1α/EMT Pathway in XCL1-Induced Migration of MDA-MB-231 and SK-BR-3 Breast Cancer Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 89
Author(s):  
Ha Thi Thu Do ◽  
Jungsook Cho
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Chemokine Receptor ◽  
Intracellular Signaling ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition

Chemokine–receptor interactions play multiple roles in cancer progression. It was reported that the overexpression of X-C motif chemokine receptor 1 (XCR1), a specific receptor for chemokine X-C motif chemokine ligand 1 (XCL1), stimulates the migration of MDA-MB-231 triple-negative breast cancer cells. However, the exact mechanisms of this process remain to be elucidated. Our study found that XCL1 treatment markedly enhanced MDA-MB-231 cell migration. Additionally, XCL1 treatment enhanced epithelial–mesenchymal transition (EMT) of MDA-MB-231 cells via E-cadherin downregulation and upregulation of N-cadherin and vimentin as well as increases in β-catenin nucleus translocation. Furthermore, XCL1 enhanced the expression of hypoxia-inducible factor-1α (HIF-1α) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Notably, the effects of XCL1 on cell migration and intracellular signaling were negated by knockdown of XCR1 using siRNA, confirming XCR1-mediated actions. Treating MDA-MB-231 cells with U0126, a specific mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, blocked XCL1-induced HIF-1α accumulation and cell migration. The effect of XCL1 on cell migration was also evaluated in ER-/HER2+ SK-BR-3 cells. XCL1 also promoted cell migration, EMT induction, HIF-1α accumulation, and ERK phosphorylation in SK-BR-3 cells. While XCL1 did not exhibit any significant impact on the matrix metalloproteinase (MMP)-2 and -9 expressions in MDA-MB-231 cells, it increased the expression of these enzymes in SK-BR-3 cells. Collectively, our results demonstrate that activation of the ERK/HIF-1α/EMT pathway is involved in the XCL1-induced migration of both MDA-MB-231 and SK-BR-3 breast cancer cells. Based on our findings, the XCL1–XCR1 interaction and its associated signaling molecules may serve as specific targets for the prevention of breast cancer cell migration and metastasis.

scholarly journals The role of protein kinase PAK1 in the regulation of estrogen-independent growth of breast cancer

2014 ◽  
Vol 60 (3) ◽  
pp. 322-331 ◽  
Author(s):  
E.A. Avilova ◽  
O.E. Andreeva ◽  
V.A. Shatskaya ◽  
M.A. Krasilnikov
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Intracellular Signaling ◽  
Breast Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Cell Lines ◽  
Hormone Resistance ◽  
Mesenchymal Transition

The main goal of this work was to study the intracellular signaling pathways responsible for the development of hormone resistance and maintaining the autonomous growth of breast cancer cells. In particular, the role of PAK1 (p21-activated kinase 1), the key mitogenic signaling protein, in the development of cell resistance to estrogens was analyzed. In vitro studies were performed on cultured breast cancer cell lines: estrogen-dependent estrogen receptor (ER)-positive MCF-7 cells and estrogen-resistant ER-negative HBL-100 cells. We found that the resistant HBL-100 cells were characterized by a higher level of PAK1 and demonstrated PAK1 involvement in the maintaining of estrogen-independent cell growth. We have also shown PAK1 ability to up-regulate Snail1, one of the epithelial-mesenchymal transition proteins, and obtained experimental evidence for Snail1 importance in the regulation of cell proliferation. In general, the results obtained in this study demonstrate involvement of PAK1 and Snail1 in the formation of estrogen-independent phenotype of breast cancer cells showing the potential role of both proteins as markers of hormone resistance of breast tumors.

scholarly journals Multi-regional characterisation of renal cell carcinoma and microenvironment at single cell resolution

2021 ◽  
Author(s):  
Ruoyan Li ◽  
John R. Ferdinand ◽  
Kevin W. Loudon ◽  
Georgina S. Bowyer ◽  
Lira Mamanova ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Function ◽  
De Novo ◽  
Epithelial Mesenchymal Transition ◽  
Spatial Location ◽  
De Novo Mutation ◽  
Cellular Interactions ◽  
Sequencing Data ◽  
Mesenchymal Transition ◽  
Multiple Regions

Tumour behaviour is dependent on the oncogenic properties of cancer cells and their multi-cellular interactions. These dependencies were examined through 270,000 single cell transcriptomes and 100 micro-dissected whole exomes obtained from 12 patients with kidney tumours. Tissue was sampled from multiple regions of tumour core, tumour-normal interface, normal surrounding tissues, and peripheral blood. We found the principal spatial location of CD8+ T cell clonotypes largely defined exhaustion state, with clonotypic heterogeneity not explained by somatic intra-tumoural heterogeneity. De novo mutation calling from single cell RNA sequencing data allows us to lineage-trace and infer clonality of cells. We discovered six meta-programmes that distinguish tumour cell function. An epithelial-mesenchymal transition meta-programme, enriched at the tumour-normal interface appears modulated through macrophage expressed IL1B, potentially forming a therapeutic target.

scholarly journals Microparticles as Potential Mediators of High Glucose-Induced Renal Cell Injury

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 348 ◽  
Author(s):  
Ravindran ◽  
Pasha ◽  
Agouni ◽  
Munusamy
Keyword(s):  
Er Stress ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Cell Injury ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Mesenchymal Transition

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-β), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-β signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN.

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