New Insights into the Molecular Mechanism of Epithelial Plasticity in Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (16 April 2023) | Viewed by 18103

Special Issue Editor


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Guest Editor
Epithelial Plasticity and Metastasis Group, Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas, Universidade da Coruña (UDC), 15006 A Coruña, Spain
Interests: cancer; epithelial plasticity; metastasis; drug resistance; small-molecule inhibitors; E3 ubiquitin-ligase; targeted therapy

Special Issue Information

Dear Colleagues, 

Epithelial cell plasticity is a reversible program that refers to the ability of epithelial cells to dynamically switch between different phenotypic cellular states. This program has been highlighted during the epithelial-to-mesenchymal transition (EMT) in tumour progression and metastasis. Tumour cells undergo EMT loose cell-cell and cell-extracellular matrix interactions, leading to cell migration and invasion. It has become evident that transcriptional, post-transcriptional, and post-translational events are critical regulators of the EMT. Moreover, in recent years, EMT has been associated to stemness and therapy resistance, critically representing one of the major challenges in oncology. Indeed, EMT has been proposed as a good therapeutic target for the designing of novel strategies against cancer. 

In this Special Issue, we focus on new molecular mechanisms implicated by the epithelial plasticity in cancer and novel therapeutic strategies against EMT to overcome drug resistance and metastasis.

Dr. Angélica Figueroa
Guest Editor

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Keywords

  • Cancer
  • Epithelial plasticity
  • Metastasis
  • Drug resistance
  • Stemness
  • Target therapy

Published Papers (7 papers)

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Research

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29 pages, 4288 KiB  
Article
A Tumor Microenvironment-Driven Network Regulated by STAT3 and p65 Negatively Controls the Enrichment of Cancer Stem Cells in Human HR+/HER2− Breast Cancer
by Hagar Ben-Yaakov, Tsipi Meshel, Metsada Pasmanik-Chor, Cindy Körner and Adit Ben-Baruch
Cancers 2023, 15(8), 2255; https://doi.org/10.3390/cancers15082255 - 12 Apr 2023
Cited by 1 | Viewed by 1696
Abstract
Hormone receptor-positive and HER2-negative (HR+/HER2−; luminal A) tumors are prevalent in breast cancer. Our past studies demonstrated that “TME Stimulation” (estrogen + TNFα + EGF, representing three arms of the tumor microenvironment, TME) has enriched metastasis-forming cancer stem cells (CSCs) in HR+/HER2− human [...] Read more.
Hormone receptor-positive and HER2-negative (HR+/HER2−; luminal A) tumors are prevalent in breast cancer. Our past studies demonstrated that “TME Stimulation” (estrogen + TNFα + EGF, representing three arms of the tumor microenvironment, TME) has enriched metastasis-forming cancer stem cells (CSCs) in HR+/HER2− human breast cancer cells. Here, following information obtained by RNAseq analyses of TME-stimulated CSCs and Non-CSCs, we found that TME Stimulation has induced the activation of S727-STAT3, Y705-STAT3, STAT1 and p65. Upon TME Stimulation, stattic (STAT3 inhibitor) usage demonstrated that Y705-STAT3 activation negatively controlled CSC enrichment and epithelial-to-mesenchymal transition (EMT) traits, while inducing CXCL8 (IL-8) and PD-L1 expression. However, STAT3 knock-down (siSTAT3) had no effect on these functions; in terms of CSC enrichment, p65 had down-regulatory roles that compensated for the loss of an entire STAT3 protein. Y705-STAT3 and p65 acted additively in reducing CSC enrichment, and Y705A-STAT3 variant + sip65 has enriched chemo-resistant CSCs. Clinical data analyses revealed an inverse correlation between Y705-STAT3 + p65 phosphorylation and CSC signature in luminal A patients, and connection to improved disease course. Overall, we find regulatory roles for Y705-STAT3 and p65 in TME-stimulated HR+/HER2− tumors, with the ability to limit CSC enrichment. These findings raise concerns about using inhibitors of STAT3 and p65 as therapeutic strategies in the clinic. Full article
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20 pages, 5745 KiB  
Article
Enhanced Epithelial-to-Mesenchymal Transition and Chemoresistance in Advanced Retinoblastoma Tumors Is Driven by miR-181a
by Vishnu Suresh Babu, Anadi Bisht, Ashwin Mallipatna, Deepak SA, Gagan Dudeja, Ramaraj Kannan, Rohit Shetty, Nilanjan Guha, Stephane Heymans and Arkasubhra Ghosh
Cancers 2022, 14(20), 5124; https://doi.org/10.3390/cancers14205124 - 19 Oct 2022
Cited by 5 | Viewed by 1990
Abstract
Advanced retinoblastoma (Rb) tumors display high metastatic spread to distant tissues, causing a potent threat to vision and life. Through transcriptomic profiling, we discovered key upregulated genes that belonged to the epithelial–mesenchymal transition (EMT) and chemotherapy resistance pathways in advanced Rb tumors. Through [...] Read more.
Advanced retinoblastoma (Rb) tumors display high metastatic spread to distant tissues, causing a potent threat to vision and life. Through transcriptomic profiling, we discovered key upregulated genes that belonged to the epithelial–mesenchymal transition (EMT) and chemotherapy resistance pathways in advanced Rb tumors. Through in vitro models, we further showed that Rb null tumor cells under prolonged chemo drug exposure, acquires a metastasis-like phenotype through the EMT program mediated by ZEB1 and SNAI2 and these cells further acquires chemotherapeutic resistance through cathepsin-L- and MDR1-mediated drug efflux mechanisms. Using a miRNA microarray, we identified miR-181a-5p as being significantly reduced in advanced Rb tumors, which was associated with an altered EMT and drug-resistance genes. We showed that enhancing miR-181a-5p levels in Rb null chemo-resistant sublines reduced the ZEB1 and SNAI2 levels and halted the mesenchymal transition switch, further reducing the drug resistance. We thus identified miR-181a-5p as a therapeutically exploitable target for EMT-triggered drug-resistant cancers that halted their invasion and migration and sensitized them to low-dose chemotherapy drugs. Full article
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22 pages, 3468 KiB  
Article
The Quasimesenchymal Pancreatic Ductal Epithelial Cell Line PANC-1—A Useful Model to Study Clonal Heterogeneity and EMT Subtype Shifting
by Hendrik Ungefroren, Isabel Thürling, Benedikt Färber, Tanja Kowalke, Tanja Fischer, Leonardo Vinícius Monteiro De Assis, Rüdiger Braun, Darko Castven, Henrik Oster, Björn Konukiewitz, Ulrich Friedrich Wellner, Hendrik Lehnert and Jens-Uwe Marquardt
Cancers 2022, 14(9), 2057; https://doi.org/10.3390/cancers14092057 - 19 Apr 2022
Cited by 10 | Viewed by 2907
Abstract
Intratumoral heterogeneity (ITH) is an intrinsic feature of malignant tumors that eventually allows a subfraction of resistant cancer cells to clonally evolve and cause therapy failure or relapse. ITH, cellular plasticity and tumor progression are driven by epithelial–mesenchymal transition (EMT) and the reverse [...] Read more.
Intratumoral heterogeneity (ITH) is an intrinsic feature of malignant tumors that eventually allows a subfraction of resistant cancer cells to clonally evolve and cause therapy failure or relapse. ITH, cellular plasticity and tumor progression are driven by epithelial–mesenchymal transition (EMT) and the reverse process, MET. During these developmental programs, epithelial (E) cells are successively converted to invasive mesenchymal (M) cells, or back to E cells, by passing through a series of intermediate E/M states, a phenomenon termed E–M plasticity (EMP). The induction of MET has clinical potential as it can block the initial EMT stages that favor tumor cell dissemination, while its inhibition can curb metastatic outgrowth at distant sites. In pancreatic ductal adenocarcinoma (PDAC), cellular models with which to study EMP or MET induction are scarce. Here, we have generated single cell-derived clonal cultures of the quasimesenchymal PDAC-derived cell line, PANC-1, and found that these differ strongly with respect to cell morphology and EMT marker expression, allowing for their tentative classification as E, E/M or M. Interestingly, the different EMT phenotypes were found to segregate with differences in tumorigenic potential in vitro, as measured by colony forming and invasive activities, and in circadian clock function. Moreover, the individual clones the phenotypes of which remained stable upon prolonged culture also responded differently to treatment with transforming growth factor (TGF)β1 in regard to regulation of growth and individual TGFβ target genes, and to culture conditions that favour ductal-to-endocrine transdifferentiation as a more direct measure for cellular plasticity. Of note, stimulation with TGFβ1 induced a shift in parental PANC-1 cultures towards a more extreme M and invasive phenotype, while exposing the cells to a combination of the proinflammatory cytokines IFNγ, IL1β and TNFα (IIT) elicited a shift towards a more E and less invasive phenotype resembling a MET-like process. Finally, we show that the actions of TGFβ1 and IIT both converge on regulating the ratio of the small GTPase RAC1 and its splice isoform, RAC1b. Our data provide strong evidence for dynamic EMT–MET transitions and qualify this cell line as a useful model with which to study EMP. Full article
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22 pages, 5894 KiB  
Article
Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival
by Alberto Vázquez-Naharro, José Bustos-Tauler, Alfredo Floristán, Lourdes Yuste, Sara S. Oltra, Antònia Vinyals, Gema Moreno-Bueno, Àngels Fabra, Francisco Portillo, Amparo Cano and Patricia G. Santamaría
Cancers 2022, 14(5), 1200; https://doi.org/10.3390/cancers14051200 - 25 Feb 2022
Cited by 8 | Viewed by 2404
Abstract
Malignant melanoma is a highly aggressive tumor causing most skin cancer-related deaths. Understanding the fundamental mechanisms responsible for melanoma progression and therapeutic evasion is still an unmet need for melanoma patients. Progression of skin melanoma and its dissemination to local or distant organs [...] Read more.
Malignant melanoma is a highly aggressive tumor causing most skin cancer-related deaths. Understanding the fundamental mechanisms responsible for melanoma progression and therapeutic evasion is still an unmet need for melanoma patients. Progression of skin melanoma and its dissemination to local or distant organs relies on phenotypic plasticity of melanoma cells, orchestrated by EMT-TFs and microphthalmia-associated TF (MITF). Recently, melanoma phenotypic switching has been proposed to uphold context-dependent intermediate cell states benefitting malignancy. LOXL3 (lysyl oxidase-like 3) promotes EMT and has a key role in human melanoma cell survival and maintenance of genomic integrity. To further understand the role of Loxl3 in melanoma, we generated a conditional Loxl3-knockout (KO) melanoma mouse model in the context of BrafV600E-activating mutation and Pten loss. Melanocyte-Loxl3 deletion increased melanoma latency, decreased tumor growth, and reduced lymph node metastatic dissemination. Complementary in vitro and in vivo studies in mouse melanoma cells confirmed Loxl3’s contribution to melanoma progression and metastasis, in part by modulating phenotypic switching through Snail1 and Prrx1 EMT-TFs. Importantly, a novel LOXL3-SNAIL1-PRRX1 axis was identified in human melanoma, plausibly relevant to melanoma cellular plasticity. These data reinforced the value of LOXL3 as a therapeutic target in melanoma. Full article
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Review

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20 pages, 2036 KiB  
Review
Unpacking the Complexity of Epithelial Plasticity: From Master Regulator Transcription Factors to Non-Coding RNAs
by Charlene Waryah, Eric Alves, Roberta Mazzieri, Riccardo Dolcetti, Erik W. Thompson, Andrew Redfern and Pilar Blancafort
Cancers 2023, 15(12), 3152; https://doi.org/10.3390/cancers15123152 - 11 Jun 2023
Cited by 1 | Viewed by 1361
Abstract
Cellular plasticity in cancer enables adaptation to selective pressures and stress imposed by the tumor microenvironment. This plasticity facilitates the remodeling of cancer cell phenotype and function (such as tumor stemness, metastasis, chemo/radio resistance), and the reprogramming of the surrounding tumor microenvironment to [...] Read more.
Cellular plasticity in cancer enables adaptation to selective pressures and stress imposed by the tumor microenvironment. This plasticity facilitates the remodeling of cancer cell phenotype and function (such as tumor stemness, metastasis, chemo/radio resistance), and the reprogramming of the surrounding tumor microenvironment to enable immune evasion. Epithelial plasticity is one form of cellular plasticity, which is intrinsically linked with epithelial–mesenchymal transition (EMT). Traditionally, EMT has been regarded as a binary state. Yet, increasing evidence suggests that EMT involves a spectrum of quasi-epithelial and quasi-mesenchymal phenotypes governed by complex interactions between cellular metabolism, transcriptome regulation, and epigenetic mechanisms. Herein, we review the complex cross-talk between the different layers of epithelial plasticity in cancer, encompassing the core layer of transcription factors, their interacting epigenetic modifiers and non-coding RNAs, and the manipulation of cancer immunogenicity in transitioning between epithelial and mesenchymal states. In examining these factors, we provide insights into promising therapeutic avenues and potential anti-cancer targets. Full article
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20 pages, 1806 KiB  
Review
Unraveling the Role of Epithelial–Mesenchymal Transition in Adenoid Cystic Carcinoma of the Salivary Glands: A Comprehensive Review
by Cosima C. Hoch, Fabian Stögbauer and Barbara Wollenberg
Cancers 2023, 15(11), 2886; https://doi.org/10.3390/cancers15112886 - 24 May 2023
Cited by 1 | Viewed by 2475
Abstract
Salivary adenoid cystic carcinoma (SACC) is considered a challenging malignancy; it is characterized by a slow-growing nature, yet a high risk of recurrence and distant metastasis, presenting significant hurdles in its treatment and management. At present, there are no approved targeted agents available [...] Read more.
Salivary adenoid cystic carcinoma (SACC) is considered a challenging malignancy; it is characterized by a slow-growing nature, yet a high risk of recurrence and distant metastasis, presenting significant hurdles in its treatment and management. At present, there are no approved targeted agents available for the management of SACC and systemic chemotherapy protocols that have demonstrated efficacy remain to be elucidated. Epithelial–mesenchymal transition (EMT) is a complex process that is closely associated with tumor progression and metastasis, enabling epithelial cells to acquire mesenchymal properties, including increased mobility and invasiveness. Several molecular signaling pathways have been implicated in the regulation of EMT in SACC, and understanding these mechanisms is crucial to identifying new therapeutic targets and developing more effective treatment approaches. This manuscript aims to provide a comprehensive overview of the latest research on the role of EMT in SACC, including the molecular pathways and biomarkers involved in EMT regulation. By highlighting the most recent findings, this review offers insights into potential new therapeutic strategies that could improve the management of SACC patients, especially those with recurrent or metastatic disease. Full article
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24 pages, 1411 KiB  
Review
Regulation of Epithelial–Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer
by Andrea Rodríguez-Alonso, Alba Casas-Pais, Daniel Roca-Lema, Begoña Graña, Gabriela Romay and Angélica Figueroa
Cancers 2020, 12(11), 3093; https://doi.org/10.3390/cancers12113093 - 23 Oct 2020
Cited by 8 | Viewed by 3524
Abstract
The epithelial–mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability [...] Read more.
The epithelial–mesenchymal plasticity (EMP) is a process by which epithelial cells acquire the ability to dynamically switch between epithelial and mesenchymal phenotypic cellular states. Epithelial cell plasticity in the context of an epithelial-to-mesenchymal transition (EMT) confers increased cell motility, invasiveness and the ability to disseminate to distant sites and form metastasis. The modulation of molecularly defined targets involved in this process has become an attractive therapeutic strategy against cancer. Protein degradation carried out by ubiquitination has gained attention as it can selectively degrade proteins of interest. In the ubiquitination reaction, the E3 ubiquitin-ligases are responsible for the specific binding of ubiquitin to a small subset of target proteins, and are considered promising anticancer drug targets. In this review, we summarize the role of the E3 ubiquitin-ligases that control targeted protein degradation in cancer-EMT, and we highlight the potential use of the E3 ubiquitin-ligases as drug targets for the development of small-molecule drugs against cancer. Full article
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