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Special Issue "New Insights into the Molecular Mechanism of Epithelial Plasticity in Cancer"

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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 9497

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Special Issue Editor

Dr. Angélica Figueroa

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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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Cancer
Epithelial plasticity
Metastasis
Drug resistance
Stemness
Target therapy

Published Papers (6 papers)

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Research

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Open AccessArticle

A Tumor Microenvironment-Driven Network Regulated by STAT3 and p65 Negatively Controls the Enrichment of Cancer Stem Cells in Human HR+/HER2− Breast Cancer

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

Viewed by 660

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 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

(This article belongs to the Special Issue New Insights into the Molecular Mechanism of Epithelial Plasticity in Cancer)

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Open AccessArticle

Enhanced Epithelial-to-Mesenchymal Transition and Chemoresistance in Advanced Retinoblastoma Tumors Is Driven by miR-181a

and

Cancers 2022, 14(20), 5124; https://doi.org/10.3390/cancers14205124 - 19 Oct 2022

Cited by 1 | Viewed by 1204

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 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

(This article belongs to the Special Issue New Insights into the Molecular Mechanism of Epithelial Plasticity in Cancer)

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Open AccessArticle

The Quasimesenchymal Pancreatic Ductal Epithelial Cell Line PANC-1—A Useful Model to Study Clonal Heterogeneity and EMT Subtype Shifting

Leonardo Vinícius Monteiro De Assis

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 4 | Viewed by 1745

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 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

(This article belongs to the Special Issue New Insights into the Molecular Mechanism of Epithelial Plasticity in Cancer)

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Open AccessArticle

Loxl3 Promotes Melanoma Progression and Dissemination Influencing Cell Plasticity and Survival

Alberto Vázquez-Naharro

and

Patricia G. Santamaría

Cancers 2022, 14(5), 1200; https://doi.org/10.3390/cancers14051200 - 25 Feb 2022

Cited by 5 | Viewed by 1637

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 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

(This article belongs to the Special Issue New Insights into the Molecular Mechanism of Epithelial Plasticity in Cancer)

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Review

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Open AccessReview

Unraveling the Role of Epithelial–Mesenchymal Transition in Adenoid Cystic Carcinoma of the Salivary Glands: A Comprehensive Review

Cosima C. Hoch

Fabian Stögbauer

and

Barbara Wollenberg

Cancers 2023, 15(11), 2886; https://doi.org/10.3390/cancers15112886 - 24 May 2023

Viewed by 470

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 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

(This article belongs to the Special Issue New Insights into the Molecular Mechanism of Epithelial Plasticity in Cancer)

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Open AccessReview

Regulation of Epithelial–Mesenchymal Plasticity by the E3 Ubiquitin-Ligases in Cancer

Andrea Rodríguez-Alonso

and

Cancers 2020, 12(11), 3093; https://doi.org/10.3390/cancers12113093 - 23 Oct 2020

Cited by 6 | Viewed by 2337

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 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

(This article belongs to the Special Issue New Insights into the Molecular Mechanism of Epithelial Plasticity in Cancer)

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