Intrinsic Balance between ZEB Family Members Is Important for Melanocyte Homeostasis and Melanoma Progression

It has become clear that cellular plasticity is a main driver of cancer therapy resistance. Consequently, there is a need to mechanistically identify the factors driving this process. The transcription factors of the zinc-finger E-box-binding homeobox family, consisting of ZEB1 and ZEB2, are notorious for their roles in epithelial-to-mesenchymal transition (EMT). However, in melanoma, an intrinsic balance between ZEB1 and ZEB2 seems to determine the cellular state by modulating the expression of the master regulator of melanocyte homeostasis, microphthalmia-associated transcription factor (MITF). ZEB2 drives MITF expression and is associated with a differentiated/proliferative melanoma cell state. On the other hand, ZEB1 is correlated with low MITF expression and a more invasive, stem cell-like and therapy-resistant cell state. This intrinsic balance between ZEB1 and ZEB2 could prove to be a promising therapeutic target for melanoma patients. In this review, we will summarise what is known on the functional mechanisms of these transcription factors. Moreover, we will look specifically at their roles during melanocyte-lineage development and homeostasis. Finally, we will overview the current literature on ZEB1 and ZEB2 in the melanoma context and link this to the ‘phenotype-switching’ model of melanoma cellular plasticity.

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Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance

Cells ◽

10.3390/cells9020428 ◽

2020 ◽

Vol 9 (2) ◽

pp. 428 ◽

Cited By ~ 12

Author(s):

József Dudás ◽

Andrea Ladányi ◽

Julia Ingruber ◽

Teresa Bernadette Steinbichler ◽

Herbert Riechelmann

Keyword(s):

T Cells ◽

Transcription Factors ◽

Tumor Cells ◽

Epithelial To Mesenchymal Transition ◽

Protein Translation ◽

Therapy Resistance ◽

Mesenchymal Transition ◽

Rna Molecules ◽

Tumor Microenvironments ◽

Micro Rnas

Epithelial to mesenchymal transition (EMT) contributes to tumor progression, cancer cell invasion, and therapy resistance. EMT is regulated by transcription factors such as the protein products of the SNAI gene family, which inhibits the expression of epithelial genes. Several signaling pathways, such as TGF-beta1, IL-6, Akt, and Erk1/2, trigger EMT responses. Besides regulatory transcription factors, RNA molecules without protein translation, micro RNAs, and long non-coding RNAs also assist in the initialization of the EMT gene cluster. A challenging novel aspect of EMT research is the investigation of the interplay between tumor microenvironments and EMT. Several microenvironmental factors, including fibroblasts and myofibroblasts, as well as inflammatory, immune, and endothelial cells, induce EMT in tumor cells. EMT tumor cells change their adverse microenvironment into a tumor friendly neighborhood, loaded with stromal regulatory T cells, exhausted CD8+ T cells, and M2 (protumor) macrophages. Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use.

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SNAI transcription factors in epithelial-to-mesenchymal transition: Comparative analysis of experimental and idiopathic pulmonary fibrosis

Pneumologie ◽

10.1055/s-2007-1032268 ◽

2007 ◽

Vol 61 (12) ◽

Author(s):

A Jayachandran ◽

M Königshoff ◽

H Yu ◽

E Rupniewska ◽

M Hecker ◽

...

Keyword(s):

Transcription Factors ◽

Comparative Analysis ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Epithelial To Mesenchymal Transition ◽

Mesenchymal Transition

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miR-204 Shifts the Epithelial to Mesenchymal Transition in Concert with the Transcription Factors RUNX2, ETS1, and cMYB in Prostate Cancer Cell Line Model

Journal of Cancer Research ◽

10.1155/2014/840906 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Krassimira Todorova ◽

Diana Zasheva ◽

Kristiyan Kanev ◽

Soren Hayrabedyan

Keyword(s):

Prostate Cancer ◽

Transcription Factors ◽

Cancer Cell ◽

Epithelial To Mesenchymal Transition ◽

Prostate Cancer Cell ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Mesenchymal Transition ◽

Cell Line Model ◽

E Cadherin

Epithelial to mesenchymal transition is an essential step in advanced cancer development. Many master transcription factors shift their expression to drive this process, while noncoding RNAs families like miR-200 are found to restrict it. In this study we investigated how the tumor suppressor miR-204 and several transcription factors modulate main markers of mesenchymal transformation like E- and N-cadherin, SLUG, VEGF, and SOX-9 in prostate cancer cell line model (LNCaP, PC3, VCaP, and NCI-H660). We found that SLUG, E-cadherin, and N-cadherin are differentially modulated by miR-204, using miR-204 specific mimics and inhibitors and siRNA gene silencing (RUNX2, ETS-1, and cMYB). The genome perturbation associated TMPRSS2-ERG fusion coincided with shift from tumor-suppressor to tumor-promoting activity of this miRNA. The ability of miR-204 to suppress cancer cell viability and migration was lost in the fusion harboring cell lines. We found differential E-cadherin splicing corroborating to miR-204 modulatory effects. RUNX2, ETS1, and cMYB are involved in the regulation of E-cadherin, N-cadherin, and VEGFA expression. RUNX2 knockdown results in SOX9 downregulation, while ETS1 and cMYB silencing result in SOX9 upregulation in VCaP cells. Their expression was found to be also methylation dependent. Our study provides means for understanding cancer heterogeneity in regard to adapted therapeutic approaches development.

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Deeper Insight in Metastatic Cancer progression;Epithelial-to-Mesenchymal Transition and Genomic Instability: implications on treatment resistance

Current Molecular Medicine ◽

10.2174/1566524021666210202114844 ◽

2021 ◽

Vol 21 ◽

Author(s):

Kenneth Omabe ◽

Sandra Uduituma ◽

David Igwe ◽

Maxwell Omabe

Keyword(s):

Dna Damage ◽

Cancer Treatment ◽

Epithelial To Mesenchymal Transition ◽

Dna Damage Repair ◽

Treatment Resistance ◽

Therapy Resistance ◽

Cellular Reprogramming ◽

Repair System ◽

Mesenchymal Transition ◽

Damage Repair

: Therapy resistance remains the major obstacle to successful cancer treatment. Epithelial-to- mesenchymal transition [EMT], a cellular reprogramming process involved in embryogenesis and organ development and regulated by a number of transcriptional factors [EMT-TFs] such as ZEB1/2, is recognized for its role in tumor progression and metastasis. Recently, a growing body of evidence has implicated EMT in cancer therapy resistance but the actual mechanism that underlie this finding has remained elusive. For example, whether it is, the EMT states in itself or the EMT-TFs that modulates chemo or radio-resistance in cancer is still contentious. Here, we summarise the molecular mechanisms of EMT program and chemotherapeutic resistance in cancer with specific reference to DNA damage response [DDR]. We provide an insight into the molecular interplay that exist between EMT program and DNA repair machinery in cancer and how this interaction influences therapeutic response. We review conflicting studies linking EMT and drug resistance via the DNA damage repair axis. We draw scientific evidence demonstrating how several molecular signalling, including EMT-TFs work in operational harmony to induce EMT and confer stemness properties on the EMT-susceptible cells. We highlight the role of enhanced DNA damage repair system associated with EMT-derived stem cell-like states in promoting therapy resistance and suggest a multi-targeting modality in combating cancer treatment resistance.

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Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820459116 ◽

2019 ◽

Vol 116 (6) ◽

pp. 2237-2242 ◽

Cited By ~ 24

Author(s):

Eva A. Ebbing ◽

Amber P. van der Zalm ◽

Anne Steins ◽

Aafke Creemers ◽

Simone Hermsen ◽

...

Keyword(s):

Esophageal Adenocarcinoma ◽

Epithelial To Mesenchymal Transition ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Treatment Resistance ◽

Serum Levels ◽

Therapy Resistance ◽

Mesenchymal Transition ◽

Dismal Prognosis ◽

Organoid Cultures

Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.

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CD47-SIRPα Signaling Induces Epithelial-Mesenchymal Transition and Cancer Stemness and Links to a Poor Prognosis in Patients with Oral Squamous Cell Carcinoma

Cells ◽

10.3390/cells8121658 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1658 ◽

Cited By ~ 5

Author(s):

Shin Pai ◽

Oluwaseun Adebayo Bamodu ◽

Yen-Kuang Lin ◽

Chun-Shu Lin ◽

Pei-Yi Chu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Transcription Factor ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Cellular Migration ◽

Mesenchymal Transition

Background: Oral squamous cell carcinoma (OSCC), with high mortality rates, is one of the most diagnosed head and neck cancers. Epithelial-to-mesenchymal transition (EMT) and the generation of cancer stem cells (CSCs) are two keys for therapy-resistance, relapse, and distant metastasis. Accumulating evidence indicates that aberrantly expressed cluster of differentiation (CD)47 is associated with cell-death evasion and metastasis; however, the role of CD47 in the generation of CSCs in OSCC is not clear. Methods: We investigated the functional roles of CD47 in OSCC cell lines SAS, TW2.6, HSC-3, and FaDu using the bioinformatics approach, immunoblotting, immunofluorescence staining, and assays for cellular migration, invasion, colony, and orosphere formation, as well as radiosensitivity. Results: We demonstrated increased expression of CD47 in OSCC patients was associated with an estimated poorly survival disadvantage (p = 0.0391) and positively correlated with the expression of pluripotency factors. Silencing CD47 significantly suppressed cell viability and orosphere formation, accompanied by a downregulated expression of CD133, SRY-Box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and c-Myc. In addition, CD47-silenced OSCC cells showed reduced EMT, migration, and clonogenicity reflected by increased E-cadherin and decreased vimentin, Slug, Snail, and N-cadherin expression. Conclusion: Of therapeutic relevance, CD47 knockdown enhanced the anti-OSCC effect of radiotherapy. Collectively, we showed an increased CD47 expression promoted the generation of CSCs and malignant OSCC phenotypes. Silencing CD47, in combination with radiation, could provide an alternative and improved therapeutic efficacy for OSCC patients.

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Posterior polymorphous corneal dystrophy – a disease caused by dysregulation of transcription factors involved in epithelial‐to‐mesenchymal transition

Acta Ophthalmologica ◽

10.1111/aos.13972_268 ◽

2018 ◽

Vol 96 (S261) ◽

pp. 73-74

Keyword(s):

Transcription Factors ◽

Epithelial To Mesenchymal Transition ◽

Corneal Dystrophy ◽

Mesenchymal Transition ◽

Posterior Polymorphous Corneal Dystrophy

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EMT Regulation by Autophagy: A New Perspective in Glioblastoma Biology

Cancers ◽

10.3390/cancers11030312 ◽

2019 ◽

Vol 11 (3) ◽

pp. 312 ◽

Cited By ~ 30

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.

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