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Cancers
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Phenotypic Plasticity and the Oncogenic Epithelial-Mesenchymal Transition
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Phenotypic Plasticity and the Oncogenic Epithelial-Mesenchymal Transition

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

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 10056

Special Issue Editor

Dr. Steven M. Frisch

E-Mail Website
Guest Editor
West Virginia University Cancer Institute and Department of Biochemistry, West Virginia University, Morgantown, WV 26506, USA
Interests: anoikis; epithelial–mesenchymal transition; epigenetics; cancer; tumor immunology; aging

Special Issue Information

Dear Colleagues,

The major underlying cause of cancer mortality is drug-resistant recurrence, usually occurring in advanced metastatic disease. Metastasis and drug resistance are driven both by genomic and epigenetic instability. For example, early stage metastatic dissemination often requires epithelial–mesenchymal transition (EMT), while this process often reverts (MET) during colonization at metastatic sites. Although studies have demonstrated that EMT can confer drug resistance, metastatic lesions are frequently and paradoxically drug resistant despite their partially restored epithelial phenotype. This state of affairs became quite confusing, until more recent studies revealed that EMT-driving transcription factors (EMT-TFs) can confer a state of phenotypic plasticity upon tumor cells. This phenomenon reflects the cells’ newly acquired ability to re-assign epigenetic marks—to increase cellular diversity—whilst bypassing normal checkpoints in the reassignment process, a bypass that has been termed “cellular pliancy” by A. Puisieux. In fact, cellular pliancy was shown to be critical to the initiating events of transformation by oncogene or tumor suppressor gene mutations. This Special Issue is thus devoted to the highly related topics of EMT and phenotypic plasticity. In particular, articles in this Special Issue will focus on the mechanisms of both EMT- and MET-driving transcription factors, how they are regulated by the tumor microenvironment, how they affect epigenetic reprogramming, and, in turn, how this reprogramming affects tumor progression with regard to metastasis, drug resistance, and tumor surveillance by the immune system.

Dr. Steven M. Frisch
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 2900 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

  • epithelial–mesenchymal transition (EMT)
  • mesenchymal–epithelial transition (MET)
  • tumor immunology
  • epigenetics
  • phenotypic plasticity
  • cellular pliancy
  • drug-resistance
  • metastasis

Published Papers (2 papers)

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Research

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16 pages, 1987 KiB  
Article
A Comparative Endocrine Trans-Differentiation Approach to Pancreatic Ductal Adenocarcinoma Cells with Different EMT Phenotypes Identifies Quasi-Mesenchymal Tumor Cells as Those with Highest Plasticity
by Paula M. Schmidtlein, Clara Volz, Rüdiger Braun, Isabel Thürling, Olha Lapshyna, Ulrich F. Wellner, Björn Konukiewitz, Hendrik Lehnert, Jens-Uwe Marquardt and Hendrik Ungefroren
Cancers 2021, 13(18), 4663; https://doi.org/10.3390/cancers13184663 - 17 Sep 2021
Cited by 4 | Viewed by 2494
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and therapy-resistant cancer types which is largely due to tumor heterogeneity, cancer cell de-differentiation, and early metastatic spread. The major molecular subtypes of PDAC are designated classical/epithelial (E) and quasi-mesenchymal (QM) subtypes, with [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and therapy-resistant cancer types which is largely due to tumor heterogeneity, cancer cell de-differentiation, and early metastatic spread. The major molecular subtypes of PDAC are designated classical/epithelial (E) and quasi-mesenchymal (QM) subtypes, with the latter having the worst prognosis. Epithelial–mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), are involved in regulating invasion/metastasis and stem cell generation in cancer cells but also early pancreatic endocrine differentiation or de-differentiation of adult pancreatic islet cells in vitro, suggesting that pancreatic ductal exocrine and endocrine cells share common EMT programs. Using a panel of PDAC-derived cell lines classified by epithelial/mesenchymal expression as either E or QM, we compared their trans-differentiation (TD) potential to endocrine progenitor or β cell-like cells since studies with human pancreatic cancer cells for possible future TD therapy in PDAC patients are not available so far. We observed that QM cell lines responded strongly to TD culture using as inducers 5′-aza-2′-deoxycytidine or growth factors/cytokines, while their E counterparts were refractory or showed only a weak response. Moreover, the gain of plasticity was associated with a decrease in proliferative and migratory activities and was directly related to epigenetic changes acquired during selection of a metastatic phenotype as revealed by TD experiments using the paired isogenic COLO 357-L3.6pl model. Our data indicate that a QM phenotype in PDAC coincides with increased plasticity and heightened trans-differentiation potential to activate a pancreatic β cell-specific transcriptional program. We strongly assume that this specific biological feature has potential to be exploited clinically in TD-based therapy to convert metastatic PDAC cells into less malignant or even benign cells. Full article
(This article belongs to the Special Issue Phenotypic Plasticity and the Oncogenic Epithelial-Mesenchymal Transition)
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Review

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18 pages, 1401 KiB  
Review
Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis
by Hadrien De Blander, Anne-Pierre Morel, Aruni P. Senaratne, Maria Ouzounova and Alain Puisieux
Cancers 2021, 13(18), 4561; https://doi.org/10.3390/cancers13184561 - 11 Sep 2021
Cited by 29 | Viewed by 6983
Abstract
Senescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the [...] Read more.
Senescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the proliferation of damaged cells. Cells undergoing senescence sustain important morphological changes, chromatin remodeling and metabolic reprogramming, and secrete pro-inflammatory factors termed senescence-associated secretory phenotype (SASP). SASP activation is required for the clearance of senescent cells by innate immunity. Therefore, escape from senescence and the associated immune editing would be a prerequisite for tumor initiation and progression as well as therapeutic resistance. One of the possible mechanisms for overcoming senescence could be the acquisition of cellular plasticity resulting from the accumulation of genomic alterations and genetic and epigenetic reprogramming. The modified composition of the SASP produced by these reprogrammed cancer cells would create a permissive environment, allowing their immune evasion. Additionally, the SASP produced by cancer cells could enhance the cellular plasticity of neighboring cells, thus hindering their recognition by the immune system. Here, we propose a comprehensive review of the literature, highlighting the role of cellular plasticity in the pro-tumoral activity of senescence in normal cells and in the cancer context. Full article
(This article belongs to the Special Issue Phenotypic Plasticity and the Oncogenic Epithelial-Mesenchymal Transition)
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