Special Issue "Mesenchymal-Epithelial Transition in Cellular Reprogramming and Cancer"

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

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editors

Dr. Jason A. Somarelli
E-Mail Website
Guest Editor
Affiliation: Director of Research, Duke Comparative Oncology Group, Duke Cancer Institute, Duke University, Durham, NC 27710, USA
Interests: cancer; evolution; ecology; comparative oncology; drug resistance; metastasis; prostate cancer; sarcoma; systems biology; molecular biology
Dr. Mohit Kumar Jolly
E-Mail Website
Guest Editor
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
Interests: metastasis; mathematical oncology; systems biology; computational biology; phenotypic plasticity; cellular decision-making; cancer stem cells; epithelial-mesenchymal transition
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Special Issue Information

Dear Colleagues,

Cellular lineages are determined by coordinated gene expression programs that direct cells toward a given fate. While almost all cells in the body maintain their lineages, some cells undergo reversible plasticity, which enables the cells to convert to a different phenotype. This phenotypic plasticity occurs during both the normal processes of development and wound healing, as well as in pathologic conditions of fibrosis and cancer metastasis. In the context of metastasis, cancer cells undergo phenotypic conversions known as epithelial plasticity. Epithelial plasticity leads to a loss of epithelial-like characteristics and a gain of either hybrid epithelial/mesenchymal/stem-like properties or a mesenchymal-like phenotype. Epithelial plasticity underlies many of the processes of metastasis. For example, phenotypic switching from epithelial to mesenchymal by way of an epithelial–mesenchymal transition (EMT) facilitates migration, invasion, and dissemination. In addition, epithelial plasticity has also been shown to be critical for the development of therapy resistance. Similarly, a reversion back to an epithelial-like state via mesenchymal–epithelial transition (MET) is thought to enable disseminated cancer cells to re-awaken the proliferative signals needed to colonize secondary sites. While the role of partial or complete EMT in metastatic dissemination and therapy resistance is well-established, the importance of a partial or complete MET as a driver of metastatic colonization and therapy resistance remains poorly understood. Recent studies have also indicated that MET is not simply a mirror image of EMT; these can be asymmetric processes in a high-dimensional molecular and/or morphological space through which the cells navigate.

In this Special Issue, we are soliciting articles from an interdisciplinary group of experts who study MET in cancer progression and other normal and pathologic processes, such as development, wound healing, and fibrosis. Articles will cover topics focused on the biomolecular and microenvironmental factors that govern EMT/MET dynamics across a range of cancers. We feel this Issue will fill an important gap in our understanding of the mechanisms underlying metastatic spread, and eventually contribute to identify new therapeutic vulnerabilities.

Dr. Jason A. Somarelli
Dr. Mohit Kumar Jolly
Guest Editors

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 papers will be 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 2200 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
  • mesenchymal–epithelial transition
  • lineage reprogramming
  • phenotypic plasticity
  • metabolism
  • tumor microenvironment
  • soluble factors
  • biomolecular drivers of plasticity
  • gene expression networks of plasticity
  • mathematical models of epithelial plasticity

Published Papers (5 papers)

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Research

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Article
KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors
Cancers 2021, 13(20), 5135; https://doi.org/10.3390/cancers13205135 - 13 Oct 2021
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Abstract
Epithelial–Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)—TWIST1/2, ZEB1/2, SNAIL1/2/3, [...] Read more.
Epithelial–Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)—TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2—are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2 and GRHL1/2). Here, using mechanism-based mathematical modeling, we show that transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote a phenotypic shift toward a more epithelial state, an observation suggested by the negative correlation of KLF4 with EMT-TFs and with transcriptomic-based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating the EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at the epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with the patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival. Full article
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Article
Identifying Molecular Signatures of Distinct Modes of Collective Migration in Response to the Microenvironment Using Three-Dimensional Breast Cancer Models
Cancers 2021, 13(6), 1429; https://doi.org/10.3390/cancers13061429 - 20 Mar 2021
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Abstract
Collective cell migration is a key feature of transition of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) among many other cancers, yet the microenvironmental factors and underlying mechanisms that trigger collective migration remain poorly understood. Here, we investigated two microenvironmental [...] Read more.
Collective cell migration is a key feature of transition of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) among many other cancers, yet the microenvironmental factors and underlying mechanisms that trigger collective migration remain poorly understood. Here, we investigated two microenvironmental factors, tumor-intrinsic hypoxia and tumor-secreted factors (secretome), as triggers of collective migration using three-dimensional (3D) discrete-sized microtumor models that recapitulate hallmarks of DCIS-IDC transition. Interestingly, the two factors induced two distinct modes of collective migration: directional and radial migration in the 3D microtumors generated from the same breast cancer cell line model, T47D. Without external stimulus, large (600 µm) T47D microtumors exhibited tumor-intrinsic hypoxia and directional migration, while small (150 µm), non-hypoxic microtumors exhibited radial migration only when exposed to the secretome of large microtumors. To investigate the mechanisms underlying hypoxia- and secretome-induced directional vs. radial migration modes, we performed differential gene expression analysis of hypoxia- and secretome-induced migratory microtumors compared with non-hypoxic, non-migratory small microtumors as controls. We propose unique gene signature sets related to tumor-intrinsic hypoxia, hypoxia-induced epithelial-mesenchymal transition (EMT), as well as hypoxia-induced directional migration and secretome-induced radial migration. Gene Set Enrichment Analysis (GSEA) and protein-protein interaction (PPI) network analysis revealed enrichment and potential interaction between hypoxia, EMT, and migration gene signatures for the hypoxia-induced directional migration. In contrast, hypoxia and EMT were not enriched in the secretome-induced radial migration, suggesting that complete EMT may not be required for radial migration. Survival analysis identified unique genes associated with low survival rate and poor prognosis in TCGA-breast invasive carcinoma dataset from our tumor-intrinsic hypoxia gene signature (CXCR4, FOXO3, LDH, NDRG1), hypoxia-induced EMT gene signature (EFEMP2, MGP), and directional migration gene signature (MAP3K3, PI3K3R3). NOS3 was common between hypoxia and migration gene signature. Survival analysis from secretome-induced radial migration identified ATM, KCNMA1 (hypoxia gene signature), and KLF4, IFITM1, EFNA1, TGFBR1 (migration gene signature) to be associated with poor survival rate. In conclusion, our unique 3D cultures with controlled microenvironments respond to different microenvironmental factors, tumor-intrinsic hypoxia, and secretome by adopting distinct collective migration modes and their gene expression analysis highlights the phenotypic heterogeneity and plasticity of epithelial cancer cells. Full article
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Review

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Review
Lineage Plasticity in Cancer: The Tale of a Skin-Walker
Cancers 2021, 13(14), 3602; https://doi.org/10.3390/cancers13143602 - 18 Jul 2021
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Abstract
Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their [...] Read more.
Lineage plasticity, the switching of cells from one lineage to another, has been recognized as a cardinal property essential for embryonic development, tissue repair and homeostasis. However, such a highly regulated process goes awry when cancer cells exploit this inherent ability to their advantage, resulting in tumorigenesis, relapse, metastasis and therapy resistance. In this review, we summarize our current understanding on the role of lineage plasticity in tumor progression and therapeutic resistance in multiple cancers. Lineage plasticity can be triggered by treatment itself and is reported across various solid as well as liquid tumors. Here, we focus on the importance of lineage switching in tumor progression and therapeutic resistance of solid tumors such as the prostate, lung, hepatocellular and colorectal carcinoma and the myeloid and lymphoid lineage switch observed in leukemias. Besides this, we also discuss the role of epithelial-mesenchymal transition (EMT) in facilitating the lineage switch in biphasic cancers such as aggressive carcinosarcomas. We also discuss the mechanisms involved, current therapeutic approaches and challenges that lie ahead in taming the scourge of lineage plasticity in cancer. Full article
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Review
Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity
Cancers 2021, 13(9), 2188; https://doi.org/10.3390/cancers13092188 - 02 May 2021
Cited by 3 | Viewed by 1079
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in [...] Read more.
Triple-negative breast cancer (TNBC) is a subtype of breast carcinoma known for its unusually aggressive behavior and poor clinical outcome. Besides the lack of molecular targets for therapy and profound intratumoral heterogeneity, the relatively quick overt metastatic spread remains a major obstacle in effective clinical management. The metastatic colonization of distant sites by primary tumor cells is affected by the microenvironment, epigenetic state of particular subclones, and numerous other factors. One of the most prominent processes contributing to the intratumoral heterogeneity is an epithelial–mesenchymal transition (EMT), an evolutionarily conserved developmental program frequently hijacked by tumor cells, strengthening their motile and invasive features. In response to various intrinsic and extrinsic stimuli, malignant cells can revert the EMT state through the mesenchymal–epithelial transition (MET), a process that is believed to be critical for the establishment of macrometastasis at secondary sites. Notably, cancer cells rarely undergo complete EMT and rather exist in a continuum of E/M intermediate states, preserving high levels of plasticity, as demonstrated in primary tumors and, ultimately, in circulating tumor cells, representing a simplified element of the metastatic cascade. In this review, we focus on cellular drivers underlying EMT/MET phenotypic plasticity and its detrimental consequences in the context of TNBC cancer. Full article
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Review
Epithelial–Mesenchymal Transition in Liver Fluke-Induced Cholangiocarcinoma
Cancers 2021, 13(4), 791; https://doi.org/10.3390/cancers13040791 - 14 Feb 2021
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Abstract
Cholangiocarcinoma (CCA) is the second most common type of hepatic cancer. In east and southeast Asia, intrahepatic CCA is caused predominantly by infection of Opisthorchis viverrini and Clonorchis sinensis, two species of parasitic liver flukes. In this review, we present molecular evidence [...] Read more.
Cholangiocarcinoma (CCA) is the second most common type of hepatic cancer. In east and southeast Asia, intrahepatic CCA is caused predominantly by infection of Opisthorchis viverrini and Clonorchis sinensis, two species of parasitic liver flukes. In this review, we present molecular evidence that liver fluke-associated CCAs have enhanced features of epithelial–mesenchymal transition (EMT) in bile duct epithelial cells (cholangiocytes) and that some of those features are associated with mis-regulation at the epigenetic level. We hypothesize that both direct and indirect mechanisms underlie parasitic infection-induced EMT in CCA. Full article
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