scholarly journals Epithelial to Mesenchymal Transition: A Challenging Playground for Translational Research. Current Models and Focus on TWIST1 Relevance and Gastrointestinal Cancers

2021 ◽  
Vol 22 (21) ◽  
pp. 11469
Author(s):  
Luana Greco ◽  
Federica Rubbino ◽  
Alessandra Morelli ◽  
Federica Gaiani ◽  
Fabio Grizzi ◽  
...  
Keyword(s):  
Translational Research ◽  
Epithelial To Mesenchymal Transition ◽  
Basic Research ◽  
Gastrointestinal Cancers ◽  
Mechanistic Studies ◽  
Hallmarks Of Cancer ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Translational Studies

Resembling the development of cancer by multistep carcinogenesis, the evolution towards metastasis involves several passages, from local invasion and intravasation, encompassing surviving anoikis into the circulation, landing at distant sites and therein establishing colonization, possibly followed by the outgrowth of macroscopic lesions. Within this cascade, epithelial to mesenchymal transition (EMT) works as a pleiotropic program enabling cancer cells to overcome local, systemic, and distant barriers against diffusion by replacing traits and functions of the epithelial signature with mesenchymal-like ones. Along the transition, a full-blown mesenchymal phenotype may not be accomplished. Rather, the plasticity of the program and its dependency on heterotopic signals implies a pendulum with oscillations towards its reversal, that is mesenchymal to epithelial transition. Cells in intermixed EÛM states can also display stemness, enabling their replication together with the epithelial reversion next to successful distant colonization. If we aim to include the EMT among the hallmarks of cancer that could modify clinical practice, the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers needs to be filled. We review the knowledge on EMT, derived from models and mechanistic studies as well as from translational studies, with an emphasis on gastrointestinal cancers (GI).

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 EMT and MET: necessary or permissive for metastasis?

2017 ◽  
Author(s):  
Mohit Kumar Jolly ◽  
Kathryn E Ware ◽  
Shivee Gilja ◽  
Jason A Somarelli ◽  
Herbert Levine
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Carcinoma Cells ◽  
Unanswered Question ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Metastatic Dissemination ◽  
Multiple Tumor ◽  
Multiple Hypotheses ◽  
Mesenchymal To Epithelial Transition ◽  
Key Questions

ABSTRACTEpithelial-to-mesenchymal transition (EMT) and its reverse mesenchymal-to-epithelial transition (MET) have been often suggested to play crucial roles in metastatic dissemination of carcinomas. Recent studies have revealed that neither of these processes is binary. Instead, carcinoma cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). While epithelial-mesenchymal plasticity has been observed pre-clinically and clinically, whether any of these phenotypic transitions are indispensable for metastatic outgrowth remains an unanswered question. Here, we focus on epithelial-mesenchymal plasticity in metastatic dissemination and propose alternative mechanisms for successful dissemination and metastases beyond the traditional EMT-MET view. We highlight multiple hypotheses that can help reconcile conflicting observations, and outline the next set of key questions that can offer valuable insights into mechanisms of metastasis in multiple tumor models.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

scholarly journals miRNA proxy approach reveals hidden functions of glycosylation

2015 ◽  
Vol 112 (23) ◽  
pp. 7327-7332 ◽  
Author(s):  
Tomasz Kurcon ◽  
Zhongyin Liu ◽  
Anika V. Paradkar ◽  
Christopher A. Vaiana ◽  
Sujeethraj Koppolu ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Epithelial To Mesenchymal Transition ◽  
Biological Function ◽  
Regulatory Elements ◽  
Rapid Identification ◽  
Mesenchymal Transition ◽  
Disease States ◽  
Mesenchymal To Epithelial Transition ◽  
Genes Encoding ◽  
Target Network

Glycosylation, the most abundant posttranslational modification, holds an unprecedented capacity for altering biological function. Our ability to harness glycosylation as a means to control biological systems is hampered by our inability to pinpoint the specific glycans and corresponding biosynthetic enzymes underlying a biological process. Herein we identify glycosylation enzymes acting as regulatory elements within a pathway using microRNA (miRNA) as a proxy. Leveraging the target network of the miRNA-200 family (miR-200f), regulators of epithelial-to-mesenchymal transition (EMT), we pinpoint genes encoding multiple promesenchymal glycosylation enzymes (glycogenes). We focus on three enzymes, beta-1,3-glucosyltransferase (B3GLCT), beta-galactoside alpha-2,3-sialyltransferase 5 (ST3GAL5), and (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 5 (ST6GALNAC5), encoding glycans that are difficult to analyze by traditional methods. Silencing these glycogenes phenocopied the effect of miR-200f, inducing mesenchymal-to-epithelial transition. In addition, all three are up-regulated in TGF-β–induced EMT, suggesting tight integration within the EMT-signaling network. Our work indicates that miRNA can act as a relatively simple proxy to decrypt which glycogenes, including those encoding difficult-to-analyze structures (e.g., proteoglycans, glycolipids), are functionally important in a biological pathway, setting the stage for the rapid identification of glycosylation enzymes driving disease states.

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

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.

scholarly journals EMT Regulation by Autophagy: A New Perspective in Glioblastoma Biology

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 312 ◽  
Author(s):  
Barbara Colella ◽  
Fiorella Faienza ◽  
Sabrina Di Bartolomeo
Keyword(s):  
Transcription Factors ◽  
Tumor Cells ◽  
Tissue Repair ◽  
Epithelial To Mesenchymal Transition ◽  
Signalling Pathways ◽  
Migration And Invasion ◽  
Cell Resistance ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
New Perspective

Epithelial-to-mesenchymal transition (EMT) and its reverse process MET naturally occur during development and in tissue repair in vertebrates. EMT is also recognized as the crucial event by which cancer cells acquire an invasive phenotype through the activation of specific transcription factors and signalling pathways. Even though glial cells have a mesenchymal phenotype, an EMT-like process tends to exacerbate it during gliomagenesis and progression to more aggressive stages of the disease. Autophagy is an evolutionary conserved degradative process that cells use in order to maintain a proper homeostasis, and defects in autophagy have been associated to several pathologies including cancer. Besides modulating cell resistance or sensitivity to therapy, autophagy also affects the migration and invasion capabilities of tumor cells. Despite this evidence, few papers are present in literature about the involvement of autophagy in EMT-like processes in glioblastoma (GBM) so far. This review summarizes the current understanding of the interplay between autophagy and EMT in cancer, with special regard to GBM model. As the invasive behaviour is a hallmark of GBM aggressiveness, defining a new link between autophagy and EMT can open a novel scenario for targeting these processes in future therapeutical approaches.

scholarly journals The Transcription Factor Elf3 Is Essential for a Successful Mesenchymal to Epithelial Transition

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 858 ◽  
Author(s):  
Burcu Sengez ◽  
Ilkin Aygün ◽  
Huma Shehwana ◽  
Neslihan Toyran ◽  
Sanem Tercan Avci ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Expression Profiles ◽  
Biological Processes ◽  
Comprehensive Understanding ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Strong Candidate ◽  
Acute Changes ◽  
Epithelial State ◽  
E Cadherin

The epithelial to mesenchymal transition (EMT) and the mesenchymal to epithelial transition (MET) are two critical biological processes that are involved in both physiological events such as embryogenesis and development and also pathological events such as tumorigenesis. They present with dramatic changes in cellular morphology and gene expression exhibiting acute changes in E-cadherin expression. Despite the comprehensive understanding of EMT, the regulation of MET is far from being understood. To find novel regulators of MET, we hypothesized that such factors would correlate with Cdh1 expression. Bioinformatics examination of several expression profiles suggested Elf3 as a strong candidate. Depletion of Elf3 at the onset of MET severely impaired the progression to the epithelial state. This MET defect was explained, in part, by the absence of E-cadherin at the plasma membrane. Moreover, during MET, ELF3 interacts with the Grhl3 promoter and activates its expression. Our findings present novel insights into the regulation of MET and reveal ELF3 as an indispensable guardian of the epithelial state. A better understanding of MET will, eventually, lead to better management of metastatic cancers.

scholarly journals β-Catenin and TGFβ signalling cooperate to maintain a mesenchymal phenotype after FosER-induced epithelial to mesenchymal transition

Oncogene ◽  
2004 ◽  
Vol 23 (15) ◽  
pp. 2672-2680 ◽  
Author(s):  
Andreas Eger ◽  
Andreas Stockinger ◽  
John Park ◽  
Elke Langkopf ◽  
Mario Mikula ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Tgfβ Signalling

scholarly journals Loss of BRMS1 Promotes a Mesenchymal Phenotype through NF-κB-Dependent Regulation ofTwist1

2014 ◽  
Vol 35 (1) ◽  
pp. 303-317 ◽  
Author(s):  
Yuan Liu ◽  
Marty W. Mayo ◽  
Aizhen Xiao ◽  
Emily H. Hall ◽  
Elianna B. Amin ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Breast Cancer Metastasis ◽  
Metastasis Suppressor ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Metastasis Suppressor 1 ◽  
Promoter Occupancy

Breast cancer metastasis suppressor 1 (BRMS1) is downregulated in non-small cell lung cancer (NSCLC), and its reduction correlates with disease progression. Herein, we investigate the mechanisms through which loss of theBRMS1gene contributes to epithelial-to-mesenchymal transition (EMT). Using a short hairpin RNA (shRNA) system, we show that loss of BRMS1 promotes basal and transforming growth factor beta-induced EMT in NSCLC cells. NSCLC cells expressingBRMS1shRNAs (BRMS1knockdown [BRMS1KD]) display mesenchymal characteristics, including enhanced cell migration and differential regulation of the EMT markers. Mesenchymal phenotypes observed inBRMS1KDcells are dependent on RelA/p65, the transcriptionally active subunit of nuclear factor kappa B (NF-κB). In addition, chromatin immunoprecipitation analysis demonstrates that loss ofBRMS1increasesTwist1promoter occupancy of RelA/p65 K310—a key histone modification associated with increased transcription. Knockdown ofTwist1results in reversal ofBRMS1KD-mediated EMT phenotypic changes. Moreover, in our animal model,BRMS1KD/Twist1KDdouble knockdown cells were less efficient in establishing lung tumors thanBRMS1KDcells. Collectively, this study demonstrates that loss of BRMS1 promotes malignant phenotypes that are dependent on NF-κB-dependent regulation ofTwist1. These observations offer fresh insight into the mechanisms through which BRMS1 regulates the development of metastases in NSCLC.

scholarly journals Cripto-1 as a Key Factor in Tumor Progression, Epithelial to Mesenchymal Transition and Cancer Stem Cells

2021 ◽  
Vol 22 (17) ◽  
pp. 9280
Author(s):  
Hilal Arnouk ◽  
Gloria Yum ◽  
Dean Shah
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Cancer Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Malignant Tumors ◽  
Lymphatic Vessels ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Skin Cancers ◽  
Key Factor

Cripto-1 is an essential protein for human development that plays a key role in the early phase of gastrulation in the differentiation of an embryo as well as assists with wound healing processes. Importantly, Cripto-1 induces epithelial to mesenchymal transition to turn fixed epithelial cells into a more mobile mesenchymal phenotype through the downregulation of epithelial adhesion molecules such as E-cadherin, occludins, and claudins, and the upregulation of mesenchymal, mobile proteins, such as N-cadherin, Snail, and Slug. Consequently, Cripto-1’s role in inducing EMT to promote cell motility is beneficial in embryogenesis, but detrimental in the formation, progression and metastasis of malignant tumors. Indeed, Cripto-1 is found to be upregulated in most cancers, such as breast, lung, gastrointestinal, hepatic, renal, cervical, ovarian, prostate, and skin cancers. Through its role in EMT, Cripto-1 can remodel cancer cells to enable them to travel through the extracellular matrix as well as blood and lymphatic vessels to metastasize to different organs. Additionally, Cripto-1 promotes the survival of cancer stem cells, which can lead to relapse in cancer patients.

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