scholarly journals Dual inhibition of TGFβ and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype

2021 ◽  
Vol 38 (3) ◽  
Author(s):  
Davide Ciardiello ◽  
Bernadette Blauensteiner ◽  
Nunzia Matrone ◽  
Valentina Belli ◽  
Thomas Mohr ◽  
...  
Keyword(s):  
In Silico Analysis ◽  
Novel Therapy ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Risk Of Recurrence ◽  
Aggressive Disease ◽  
Tgfβ Receptors ◽  
Increased Risk ◽  
Dual Inhibition

AbstractA subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGFβ signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGFβ inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGFβ as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGFβ receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGFβ galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGFβ receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGFβ could represent a novel therapeutic strategy for patients with this aggressive disease.

The role of DUBs in the post-translational control of cell migration

2019 ◽  
Vol 63 (5) ◽  
pp. 579-594 ◽  
Author(s):  
Guillem Lambies ◽  
Antonio García de Herreros ◽  
Víctor M. Díaz
Keyword(s):  
Cell Migration ◽  
Translational Control ◽  
Epithelial To Mesenchymal Transition ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Tgfβ Receptors ◽  
Fundamental Process ◽  
Multistep Process

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.

scholarly journals Notch-Jagged signalling can give rise to clusters of cells exhibiting a hybrid epithelial/mesenchymal phenotype

2016 ◽  
Vol 13 (118) ◽  
pp. 20151106 ◽  
Author(s):  
Marcelo Boareto ◽  
Mohit Kumar Jolly ◽  
Aaron Goldman ◽  
Mika Pietilä ◽  
Sendurai A. Mani ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
Cell Communication ◽  
Notch Signalling ◽  
Circulating Tumour Cells ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Key Players

Metastasis can involve repeated cycles of epithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition. Cells can also undergo partial transitions to attain a hybrid epithelial/mesenchymal (E/M) phenotype that allows the migration of adhering cells to form a cluster of circulating tumour cells. These clusters can be apoptosis-resistant and possess an increased metastatic propensity as compared to the cells that undergo a complete EMT (mesenchymal cells). Hence, identifying the key players that can regulate the formation and maintenance of such clusters may inform anti-metastasis strategies. Here, we devise a mechanism-based theoretical model that links cell–cell communication via Notch-Delta-Jagged signalling with the regulation of EMT. We demonstrate that while both Notch-Delta and Notch-Jagged signalling can induce EMT in a population of cells, only Jagged-dominated Notch signalling, but not Delta-dominated signalling, can lead to the formation of clusters containing hybrid E/M cells. Our results offer possible mechanistic insights into the role of Jagged in tumour progression, and offer a framework to investigate the effects of other microenvironmental signals during metastasis.

scholarly journals The Epithelial–Mesenchymal Transition at the Crossroads between Metabolism and Tumor Progression

2022 ◽  
Vol 23 (2) ◽  
pp. 800
Author(s):  
Monica Fedele ◽  
Riccardo Sgarra ◽  
Sabrina Battista ◽  
Laura Cerchia ◽  
Guidalberto Manfioletti
Keyword(s):  
Tumor Progression ◽  
Cancer Progression ◽  
Energy Demand ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Epithelial Phenotype ◽  
Plastic Process ◽  
Mesenchymal Epithelial Transition

The transition between epithelial and mesenchymal phenotype is emerging as a key determinant of tumor cell invasion and metastasis. It is a plastic process in which epithelial cells first acquire the ability to invade the extracellular matrix and migrate into the bloodstream via transdifferentiation into mesenchymal cells, a phenomenon known as epithelial–mesenchymal transition (EMT), and then reacquire the epithelial phenotype, the reverse process called mesenchymal–epithelial transition (MET), to colonize a new organ. During all metastatic stages, metabolic changes, which give cancer cells the ability to adapt to increased energy demand and to withstand a hostile new environment, are also important determinants of successful cancer progression. In this review, we describe the complex interaction between EMT and metabolism during tumor progression. First, we outline the main connections between the two processes, with particular emphasis on the role of cancer stem cells and LncRNAs. Then, we focus on some specific cancers, such as breast, lung, and thyroid cancer.

scholarly journals Epithelial-Mesenchymal Transition in Pancreatic Cancer: A Review

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Shuai Wang ◽  
Shuai Huang ◽  
Yu Ling Sun
Keyword(s):  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Ductal Adenocarcinoma ◽  
Current Therapy ◽  
Solid Cancer ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Complex Processes ◽  
Solid Malignancies

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies and is characterized by its insensitivity to current therapy. The invasion and metastasis of solid tumors such as PDAC are complex processes involving many factors. Recent insights into the role of cancer stem cells (CSCs) and the epithelial-mesenchymal transition (EMT) in tumorigenesis have increased the knowledge base and highlighted new therapeutic targets of this disease. The process of EMT is regulated by a complex network of cytokines, transcription factors, growth factors, signaling pathways, and the tumor microenvironment, exhibiting CSC-like properties. The transition of solid cancer cells from an epithelial to a mesenchymal phenotype increases their migratory and invasive properties, thus promoting metastasis. In PDAC, the exact influence of EMT on the biological behaviors of cancer cells and its impact on clinical therapy remain controversial, but the therapeutic strategy of combining EMT inhibition with chemotherapy deserves attention. Alternatively, anti-inflammatory therapy that targets the interaction between inflammation and EMT is a valid strategy for treating the premalignant stage of tumor progression. In this review, we summarize the latest research on EMT and the potential relationship between EMT and PDAC.

scholarly journals E-Cadherin in Pancreatic Ductal Adenocarcinoma: A Multifaceted Actor during EMT

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1040 ◽  
Author(s):  
Michele Sommariva ◽  
Nicoletta Gagliano
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Ductal Adenocarcinoma ◽  
Down Regulation ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Cytoskeleton Reorganization ◽  
Tumor Cell Behavior ◽  
Open Question ◽  
E Cadherin

Epithelial-to-mesenchymal transition (EMT) is a step-wise process observed in normal and tumor cells leading to a switch from epithelial to mesenchymal phenotype. In tumors, EMT provides cancer cells with a metastatic phenotype characterized by E-cadherin down-regulation, cytoskeleton reorganization, motile and invasive potential. E-cadherin down-regulation is known as a key event during EMT. However, E-cadherin expression can be influenced by the different experimental settings and environmental stimuli so that the paradigm of EMT based on the loss of E-cadherin determining tumor cell behavior and fate often becomes an open question. In this review, we aimed at focusing on some critical points in order to improve the knowledge of the dynamic role of epithelial cells plasticity in EMT and, specifically, address the role of E-cadherin as a marker for the EMT axis.

scholarly journals Splice-Variant Knock-Out of TGFβ Receptors Perturbates the Proteome of Ovarian Carcinoma Cells

2021 ◽  
Vol 22 (23) ◽  
pp. 12647
Author(s):  
Liora Jacobs Catane ◽  
Ofra Moshel ◽  
Yoav Smith ◽  
Ben Davidson ◽  
Reuven Reich
Keyword(s):  
Ovarian Carcinoma ◽  
Proteomic Analysis ◽  
Transforming Growth Factor ◽  
Biological Role ◽  
Mrna Levels ◽  
Cellular Motility ◽  
Mesenchymal Transition ◽  
Tgfβ Receptors ◽  
Tgfβ Receptor

The aim of this study was to analyze the biological role of different transforming growth factor-β (TGFβ) receptor splice variants in ovarian carcinoma (OC). Specific receptor variant knockouts (KO) were prepared using the CRISPR/Cas9 genome editing system in two OC cell lines, TβRI variant 1 (TβRIv1) KO in ES-2 cells and TβRII variant 1 (TβRIIv1) KO in OVCAR-8 cells. Control and KO cells were compared by proteomic analysis, functional tests, analysis of epithelial–mesenchymal transition (EMT) drivers, and Western blot of signaling proteins. Proteomic analysis revealed significant changes in protein pathways in the KO cells. TβRIv1 KO resulted in a significant reduction in both cellular motility and invasion, while TβRIIv1 KO significantly reduced cellular motility and increased Reactive Oxygen Species (ROS) production. Both receptor variant KOs reduced MET protein levels. Of the EMT drivers, a significant decrease in TWIST protein expression, and increase in SNAIL protein and MALAT1 mRNA levels were observed in the TβRIIv1 KO compared to control. A significant decrease in JNK1 and JNK2 activation was found in the TβRIv1 KO compared to control cells. These findings provide new insight regarding the biological role of the TGFβ receptor variants in the biology and potentially the progression of OC.

scholarly journals Twist1 Influences the Expression of Leading Members of the IL-17 Signaling Pathway in HER2-Positive Breast Cancer Cells

2021 ◽  
Vol 22 (22) ◽  
pp. 12144
Author(s):  
Bruno R. B. Pires ◽  
Renata Binato ◽  
Gerson M. Ferreira ◽  
Stephany Corrêa ◽  
Bárbara Du Rocher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
In Silico Analysis ◽  
Molecular Characteristics ◽  
Her2 Positive ◽  
Mesenchymal Transition ◽  
Metastatic Process ◽  
Silico Analysis

Breast cancer (BC) is a heterogeneous disease composed of multiple subtypes with different molecular characteristics and clinical outcomes. The metastatic process in BC depends on the transcription factors (TFs) related to epithelial-mesenchymal transition (EMT), including the master regulator Twist1. However, its role beyond EMT in BC subtypes remains unclear. Our study aimed to investigate the role of Twist1, beyond EMT, in the molecular subtypes of BC. In patients, we observed the overexpression of TWIST1 in the HER2+ group. The silencing of TWIST1 in HER2+ BC cells resulted in the upregulation of 138 genes and the downregulation of 174 genes compared to control cells in a microarray assay. In silico analysis revealed correlations between Twist1 and important biological processes such as the Th17-mediated immune response, suggesting that Twist1 could be relevant for IL-17 signaling in HER2+ BC. IL-17 signaling was then examined, and it was shown that TWIST1 knockdown caused the downregulation of leading members of IL-17 signaling pathway. Taken together, our findings suggest that Twist1 plays a role on IL-17 signaling in HER2+ BC.

scholarly journals Neddylation blockade induces HIF-1α driven cancer cell migration via upregulation of ZEB1

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jun Bum Park ◽  
Jieun Seo ◽  
Jong-Wan Park ◽  
Yang-Sook Chun
Keyword(s):  
Cell Migration ◽  
Cancer Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Enzymatic Reaction ◽  
Akt Pathway ◽  
Cancer Cell Migration ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition

Abstract Neddylation is a process by which NEDD8 is covalently conjugated to target proteins by sequential enzymatic reaction. Its role in cancer cell migration has only been recently acknowledged. Previously in cancer cell migration, the epithelial to mesenchymal transition (EMT) process has been well-known to play an important role in both invasion and metastasis by promoting mesenchymal phenotype in epithelial cells. However, the role of neddylation in the EMT process and its mechanistic details are yet to be elucidated. We recently reported that neddylation plays a crucial role in cancer cell migration through the PI3K-Akt pathway. Here, we report that inhibiting neddylation activates the hypoxia-inducible factor 1α (HIF-1α) through the PI3K-Akt pathway, which eventually regulates the EMT-activator ZEB1 (zinc finger E-box binding homeobox 1) in various cancer cell lines. As induction of HIF-1α is known to deteriorate the state of cancer and EMT process is one of the hallmarks of metastasis in cancer, our findings uncover the role of neddylation between HIF-1α and ZEB1.

scholarly journals WDR5 inhibition halts metastasis dissemination by repressing the mesenchymal phenotype of breast cancer cells

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Simona Punzi ◽  
Chiara Balestrieri ◽  
Carolina D’Alesio ◽  
Daniela Bossi ◽  
Gaetano Ivan Dellino ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Targeting ◽  
Breast Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Triple Negative ◽  
Systemic Treatment ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Luminal B

Abstract Background Development of metastases and drug resistance are still a challenge for a successful systemic treatment in breast cancer (BC) patients. One of the mechanisms that confer metastatic properties to the cell relies in the epithelial-to-mesenchymal transition (EMT). Moreover, both EMT and metastasis are partly modulated through epigenetic mechanisms, by repression or induction of specific related genes. Methods We applied shRNAs and drug targeting approaches in BC cell lines and metastatic patient-derived xenograft (PDX) models to inhibit WDR5, the core subunit of histone H3 K4 methyltransferase complexes, and evaluate its role in metastasis regulation. Result We report that WDR5 is crucial in regulating tumorigenesis and metastasis spreading during BC progression. In particular, WDR5 loss reduces the metastatic properties of the cells by reverting the mesenchymal phenotype of triple negative- and luminal B-derived cells, thus inducing an epithelial trait. We also suggest that this regulation is mediated by TGFβ1, implying a prominent role of WDR5 in driving EMT through TGFβ1 activation. Moreover, such EMT reversion can be induced by drug targeting of WDR5 as well, leading to BC cell sensitization to chemotherapy and enhancement of paclitaxel-dependent effects. Conclusions We suggest that WDR5 inhibition could be a promising pharmacologic approach to reduce cell migration, revert EMT, and block metastasis formation in BC, thus overcoming resistance to standard treatments.

scholarly journals Epithelial to Mesenchymal Transition in a Clinical Perspective

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jennifer Pasquier ◽  
Nadine Abu-Kaoud ◽  
Haya Al Thani ◽  
Arash Rafii
Keyword(s):  
General Circulation ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Phenotype ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Tumor Phenotype ◽  
Therapeutic Context ◽  
Aggressive Tumor ◽  
Made In

Tumor growth and metastatic dissemination rely on cellular plasticity. Among the different phenotypes acquired by cancer cells, epithelial to mesenchymal transition (EMT) has been extensively illustrated. Indeed, this transition allows an epithelial polarized cell to acquire a more mesenchymal phenotype with increased mobility and invasiveness. The role of EMT is quite clear during developmental stage. In the neoplastic context in many tumors EMT has been associated with a more aggressive tumor phenotype including local invasion and distant metastasis. EMT allows the cell to invade surrounding tissues and survive in the general circulation and through a stem cell phenotype grown in the host organ. The molecular pathways underlying EMT have also been clearly defined and their description is beyond the scope of this review. Here we will summarize and analyze the attempts made to block EMT in the therapeutic context. Indeed, till today, most of the studies are made in animal models. Few clinical trials are ongoing with no obvious benefits of EMT inhibitors yet. We point out the limitations of EMT targeting such tumor heterogeneity or the dynamics of EMT during disease progression.

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