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

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.

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Oncogenic Role of Exosomal Circular and Long Noncoding RNAs in Gastrointestinal Cancers

International Journal of Molecular Sciences ◽

10.3390/ijms23020930 ◽

2022 ◽

Vol 23 (2) ◽

pp. 930

Author(s):

Ba Da Yun ◽

Ye Ji Choi ◽

Seung Wan Son ◽

Gabriel Adelman Cipolla ◽

Fernanda Costa Brandão Berti ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Cell Communication ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Circular Rnas ◽

Gastrointestinal Cancers ◽

Gastrointestinal Malignancies ◽

Mesenchymal Transition ◽

Novel Therapeutic Strategies

Circular RNAs (circRNAs) and long noncoding RNAs (lncRNAs) are differentially expressed in gastrointestinal cancers. These noncoding RNAs (ncRNAs) regulate a variety of cellular activities by physically interacting with microRNAs and proteins and altering their activity. It has also been suggested that exosomes encapsulate circRNAs and lncRNAs in cancer cells. Exosomes are then discharged into the extracellular environment, where they are taken up by other cells. As a result, exosomal ncRNA cargo is critical for cell–cell communication within the cancer microenvironment. Exosomal ncRNAs can regulate a range of events, such as angiogenesis, metastasis, immune evasion, drug resistance, and epithelial-to-mesenchymal transition. To set the groundwork for developing novel therapeutic strategies against gastrointestinal malignancies, a thorough understanding of circRNAs and lncRNAs is required. In this review, we discuss the function and intrinsic features of oncogenic circRNAs and lncRNAs that are enriched within exosomes.

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The Mechanisms of Colorectal Cancer Cell mesenchymal-epithelial Transition Induced by Hepatocyte Exosome-derived miR-203a-3p

10.21203/rs.3.rs-147649/v1 ◽

2021 ◽

Author(s):

Heyang Xu ◽

Qiusheng Lan ◽

Yongliang Huang ◽

Yang Zhang ◽

Yujie Zeng ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Real Time Quantitative Pcr ◽

Mesenchymal To Epithelial Transition ◽

Reporter Assays ◽

Phosphatase Of Regenerating Liver

Abstract Background: Liver metastasis is the most common cause of death in patients with colorectal cancer (CRC). Phosphatase of regenerating liver-3 induces CRC metastasis by epithelial-to-mesenchymal transition, which promotes CRC cell liver metastasis. Mesenchymal-to-epithelial transition (MET), the opposite of epithelial-to-mesenchymal transition, has been proposed as a mechanism for the establishment of metastatic neoplasms. However, the molecular mechanism of MET remains unclear. Methods: Using Immunohistochemistry, western blotting，invasion assays, real-time quantitative PCR, chromatin immunoprecipitation, luciferase reporter assays, human miRNA arrays, and xenograft mouse model, we determined the role of hepatocyte exosome-derived miR-203a-3p in CRC MET.Results: In our study, we found that miR-203a-3p derived from hepatocyte exosomes increased colorectal cancer cells E-cadherin expression, inhibited Src expression, and reduced activity. In this way miR-203a-3p induced the decreased invasion rate of CRC cells.Coclusion: MiR-203a-3p derived from hepatocyte exosomes plays an important role of CRC cells to colonize in liver.

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ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

Journal of Clinical Medicine ◽

10.3390/jcm10153373 ◽

2021 ◽

Vol 10 (15) ◽

pp. 3373

Author(s):

Margherita Sisto ◽

Domenico Ribatti ◽

Sabrina Lisi

Keyword(s):

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Tumour Progression ◽

Smooth Muscle Actin ◽

Mesenchymal Transition ◽

Inflammatory Conditions ◽

Fibrotic Process ◽

Factor Α ◽

Necrosis Factor

For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.

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Craniofacial transitions: the role of EMT and MET during head development

Development ◽

10.1242/dev.196030 ◽

2021 ◽

Vol 148 (4) ◽

pp. dev196030

Author(s):

Natalie J. Milmoe ◽

Abigail S. Tucker

Keyword(s):

Neural Crest ◽

Cell Fate ◽

Epithelial To Mesenchymal Transition ◽

Neural Crest Cells ◽

Molecular Changes ◽

Mesenchymal Transition ◽

Head Development ◽

Mesenchymal To Epithelial Transition

ABSTRACTWithin the developing head, tissues undergo cell-fate transitions to shape the forming structures. This starts with the neural crest, which undergoes epithelial-to-mesenchymal transition (EMT) to form, amongst other tissues, many of the skeletal tissues of the head. In the eye and ear, these neural crest cells then transform back into an epithelium, via mesenchymal-to-epithelial transition (MET), highlighting the flexibility of this population. Elsewhere in the head, the epithelium loses its integrity and transforms into mesenchyme. Here, we review these craniofacial transitions, looking at why they happen, the factors that trigger them, and the cell and molecular changes they involve. We also discuss the consequences of aberrant EMT and MET in the head.

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The mechanisms of colorectal cancer cell mesenchymal-epithelial transition induced by hepatocyte exosome-derived miR-203a-3p

BMC Cancer ◽

10.1186/s12885-021-08419-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Heyang Xu ◽

Qiusheng Lan ◽

Yongliang Huang ◽

Yang Zhang ◽

Yujie Zeng ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Real Time Quantitative Pcr ◽

Mesenchymal To Epithelial Transition ◽

Reporter Assays ◽

Phosphatase Of Regenerating Liver

Abstract Background Liver metastasis is the most common cause of death in patients with colorectal cancer (CRC). Phosphatase of regenerating liver-3 induces CRC metastasis by epithelial-to-mesenchymal transition, which promotes CRC cell liver metastasis. Mesenchymal-to-epithelial transition (MET), the opposite of epithelial-to-mesenchymal transition, has been proposed as a mechanism for the establishment of metastatic neoplasms. However, the molecular mechanism of MET remains unclear. Methods Using Immunohistochemistry, western blotting, invasion assays, real-time quantitative PCR, chromatin immunoprecipitation, luciferase reporter assays, human miRNA arrays, and xenograft mouse model, we determined the role of hepatocyte exosome-derived miR-203a-3p in CRC MET. Results In our study, we found that miR-203a-3p derived from hepatocyte exosomes increased colorectal cancer cells E-cadherin expression, inhibited Src expression, and reduced activity. In this way miR-203a-3p induced the decreased invasion rate of CRC cells. Coclusion MiR-203a-3p derived from hepatocyte exosomes plays an important role of CRC cells to colonize in liver.

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Exosome-Mediated Signaling in Epithelial to Mesenchymal Transition and Tumor Progression

Journal of Clinical Medicine ◽

10.3390/jcm8010026 ◽

2018 ◽

Vol 8 (1) ◽

pp. 26 ◽

Cited By ~ 23

Author(s):

Alice Conigliaro ◽

Carla Cicchini

Keyword(s):

Tumor Progression ◽

Intercellular Communication ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Cell Communication ◽

Therapeutic Approaches ◽

Mesenchymal Transition ◽

Rna Molecules ◽

Dna And Rna

Growing evidence points to exosomes as key mediators of cell–cell communication, by transferring their specific cargo (e.g., proteins, lipids, DNA and RNA molecules) from producing to receiving cells. In cancer, the regulation of the exosome-mediated intercellular communication may be reshaped, inducing relevant changes in gene expression of recipient cells in addition to microenvironment alterations. Notably, exosomes may deliver signals able to induce the transdifferentiation process known as Epithelial-to-Mesenchymal Transition (EMT). In this review, we summarize recent findings on the role of exosomes in tumor progression and EMT, highlighting current knowledge on exosome-mediated intercellular communication in tumor-niche establishment, migration, invasion, and metastasis processes. This body of evidence suggests the relevance of taking into account exosome-mediated signaling and its multifaceted aspects to develop innovative anti-tumoral therapeutic approaches.

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

Cells ◽

10.3390/cells9041040 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1040 ◽

Cited By ~ 10

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.

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

Scientific Reports ◽

10.1038/s41598-020-75286-0 ◽

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.

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

Breast Cancer Research ◽

10.1186/s13058-019-1216-y ◽

2019 ◽

Vol 21 (1) ◽

Cited By ~ 4

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.

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Epithelial to Mesenchymal Transition in a Clinical Perspective

Journal of Oncology ◽

10.1155/2015/792182 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 40

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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