scholarly journals Genetic and Genomic Pathways of Melanoma Development, Invasion and Metastasis

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1543
Author(s):  
Jyoti Motwani ◽  
Michael R. Eccles
Keyword(s):  
Skin Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Model ◽  
Tumour Progression ◽  
Clonal Evolution ◽  
Genetic Alterations ◽  
Invasion And Metastasis ◽  
Tumour Heterogeneity ◽  
Mesenchymal Transition ◽  
Phenotype Switching

Melanoma is a serious form of skin cancer that accounts for 80% of skin cancer deaths. Recent studies have suggested that melanoma invasiveness is attributed to phenotype switching, which is a reversible type of cell behaviour with similarities to epithelial to mesenchymal transition. Phenotype switching in melanoma is reported to be independent of genetic alterations, whereas changes in gene transcription, and epigenetic alterations have been associated with invasiveness in melanoma cell lines. Here, we review mutational, transcriptional, and epigenomic alterations that contribute to tumour heterogeneity in melanoma, and their potential to drive melanoma invasion and metastasis. We also discuss three models that are hypothesized to contribute towards aspects of tumour heterogeneity and tumour progression in melanoma, namely the clonal evolution model, the cancer stem cell model, and the phenotype switching model. We discuss the merits and disadvantages of each model in explaining tumour heterogeneity in melanoma, as a precursor to invasion and metastasis.

scholarly journals Functional Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2823
Author(s):  
Ian M. Overton ◽  
Andrew H. Sims ◽  
Jeremy A. Owen ◽  
Bret S. E. Heale ◽  
Matthew J. Ford ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Networks ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Cell Model ◽  
Tumour Progression ◽  
Mesenchymal Transition ◽  
Transcription Factor Target ◽  
Network Modules ◽  
Conserved Gene

Cell identity is governed by gene expression, regulated by transcription factor (TF) binding at cis-regulatory modules. Decoding the relationship between TF binding patterns and gene regulation is nontrivial, remaining a fundamental limitation in understanding cell decision-making. We developed the NetNC software to predict functionally active regulation of TF targets; demonstrated on nine datasets for the TFs Snail, Twist, and modENCODE Highly Occupied Target (HOT) regions. Snail and Twist are canonical drivers of epithelial to mesenchymal transition (EMT), a cell programme important in development, tumour progression and fibrosis. Predicted “neutral” (non-functional) TF binding always accounted for the majority (50% to 95%) of candidate target genes from statistically significant peaks and HOT regions had higher functional binding than most of the Snail and Twist datasets examined. Our results illuminated conserved gene networks that control epithelial plasticity in development and disease. We identified new gene functions and network modules including crosstalk with notch signalling and regulation of chromatin organisation, evidencing networks that reshape Waddington’s epigenetic landscape during epithelial remodelling. Expression of orthologous functional TF targets discriminated breast cancer molecular subtypes and predicted novel tumour biology, with implications for precision medicine. Predicted invasion roles were validated using a tractable cell model, supporting our approach.

Abstract 1820: TP63 regulation of epithelial to mesenchymal transition in an experimental prostate cell model.

2013 ◽  
Author(s):  
Jan Roger Olsen ◽  
Anne Margrete Øyan ◽  
Kari Rostad ◽  
Margrete R. Hellem ◽  
Jie Liu ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Cell Model ◽  
Prostate Cell ◽  
Mesenchymal Transition

Molecular Pathways in Head and Neck Cancer: EGFR, PI3K, and More

2013 ◽  
pp. 246-255 ◽  
Author(s):  
Amanda Psyrri ◽  
Tanguy Y. Seiwert ◽  
Antonio Jimeno
Keyword(s):  
Head And Neck ◽  
Epithelial To Mesenchymal Transition ◽  
Resistance Mechanism ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Mesenchymal Transition ◽  
Novel Treatment ◽  
Pathway Activation ◽  
Novel Target ◽  
Targeting Strategy

The treatment of head and neck squamous cell carcinoma (HNSCC) is set to undergo rapid changes, as novel treatment targets informed by genomic profiling and novel molecularly targeted therapies continue to make strides. In this review we provide an overview of the latest developments regarding (1) EGFR targeting for HNSCC, (2) PI3K as a novel treatment target, and (3) newly described key genetic events in HNSCC such as NOTCH1 mutations and emerging candidate targets including ALK1 and hedgehog. The first molecular targeting strategy to demonstrate a survival advantage for patients with HNSCC has emerged in the context of EGFR biology. Cetuximab remains the only U.S. Food and Drug Administration (FDA)-approved targeted therapy available for HNSCC, but EGFR as a target has not been individualized in this disease. The PI3K-AKT pathway is downstream of EGFR and is emerging as potentially one of the most important pathways in HNSCC. PIK3CA is the most frequently mutated oncogene for HNSCC (approximately 20%) and may play a role for both HPV-negative and HPV-positive tumors. Multiple therapeutic strategies targeting PI3K are being explored, and multiple agents either alone or in combination are in development. NOTCH1 is a key tumor suppressor gene and its genetic alterations lead to abnormal pathway activation. ALK1 is a novel target involved in angiogenesis, and efficacy in patients with HNSCC was documented in an early inhibitor trial. The hedgehog pathway modulates EGFR dependence and epithelial to mesenchymal transition (EMT), a key invasion and drug-resistance mechanism in HNSCC.

scholarly journals Hakin-1, a New Specific Small-Molecule Inhibitor for the E3 Ubiquitin-Ligase Hakai, Inhibits Carcinoma Growth and Progression

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1340 ◽  
Author(s):  
Olaia Martinez-Iglesias ◽  
Alba Casas-Pais ◽  
Raquel Castosa ◽  
Andrea Díaz-Díaz ◽  
Daniel Roca-Lema ◽  
...  
Keyword(s):  
Small Molecule ◽  
Ubiquitin Ligase ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
E3 Ubiquitin Ligase ◽  
Therapeutic Drug ◽  
Mesenchymal Transition ◽  
E Cadherin

The requirement of the E3 ubiquitin-ligase Hakai for the ubiquitination and subsequent degradation of E-cadherin has been associated with enhanced epithelial-to-mesenchymal transition (EMT), tumour progression and carcinoma metastasis. To date, most of the reported EMT-related inhibitors were not developed for anti-EMT purposes, but indirectly affect EMT. On the other hand, E3 ubiquitin-ligase enzymes have recently emerged as promising therapeutic targets, as their specific inhibition would prevent wider side effects. Given this background, a virtual screening was performed to identify novel specific inhibitors of Hakai, targeted against its phosphotyrosine-binding pocket, where phosphorylated-E-cadherin specifically binds. We selected a candidate inhibitor, Hakin-1, which showed an important effect on Hakai-induced ubiquitination. Hakin-1 also inhibited carcinoma growth and tumour progression both in vitro, in colorectal cancer cell lines, and in vivo, in a tumour xenograft mouse model, without apparent systemic toxicity in mice. Our results show for the first time that a small molecule putatively targeting the E3 ubiquitin-ligase Hakai inhibits Hakai-dependent ubiquitination of E-cadherin, having an impact on the EMT process. This represents an important step forward in a future development of an effective therapeutic drug to prevent or inhibit carcinoma tumour progression.

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 Ma Xing Shi Gan Decoction Protects against PM2.5-Induced Lung Injury through Suppression of Epithelial-to-Mesenchymal Transition (EMT) and Epithelial Barrier Disruption

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Ye-fang Wang ◽  
Yu-xiang Fei ◽  
Bo Zhao ◽  
Qi-yang Yin ◽  
Jian-ping Zhu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Model ◽  
Alveolar Epithelial Cell ◽  
Epithelial Barrier ◽  
Barrier Dysfunction ◽  
Mesenchymal Transition ◽  
Epithelial Barrier Dysfunction

This research was designed to explore the effect of Ma Xing Shi Gan decoction (MXD) in alleviating particulate matter less than 2.5 μm in diameter (PM2.5) induced lung injury from the perspective of epithelial barrier protection and inhibition of epithelial-to-mesenchymal transition (EMT). Rats were exposed to PM2.5 to establish a lung injury model in vivo, and a PM2.5-stimulated primary cultured type II alveolar epithelial cell model was introduced in vitro. Our results indicated that MXD alleviated the weight loss and pathologic changes and improved the epithelial barrier dysfunction. MXD also significantly inhibited the TGF-β/Smad3 pathway, increased the level of ZO-1 and claudin-5, and reversed the EMT process. Notably, the protection of MXD was abolished by TGF-β in vitro. Our results indicated that MXD has a protection against PM2.5-induced lung injury. The proposed mechanism is reversing PM2.5-induced EMT through inhibiting TGF-β/Smad3 pathway and then upregulating the expression of tight-junction proteins.

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