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: closed (31 December 2021) | Viewed by 35505

Special Issue Editors


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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

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Guest Editor
Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, 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

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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 (8 papers)

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Research

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26 pages, 28053 KiB  
Article
CTCF Expression and Dynamic Motif Accessibility Modulates Epithelial–Mesenchymal Gene Expression
by Kelsey S. Johnson, Shaimaa Hussein, Priyanka Chakraborty, Arvind Muruganantham, Sheridan Mikhail, Giovanny Gonzalez, Shuxuan Song, Mohit Kumar Jolly, Michael J. Toneff, Mary Lauren Benton, Yin C. Lin and Joseph H. Taube
Cancers 2022, 14(1), 209; https://doi.org/10.3390/cancers14010209 - 1 Jan 2022
Cited by 15 | Viewed by 4890
Abstract
Epithelial–mesenchymal transition (EMT) and its reversal, mesenchymal–epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET, or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and [...] Read more.
Epithelial–mesenchymal transition (EMT) and its reversal, mesenchymal–epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET, or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular phenotypes during stepwise reversible EMT. We find that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET, and is lower in triple-negative breast cancer cell lines with EMT features. Through an analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs, but also by a diminished enrichment for CTCF binding motifs. Through a loss-of-function analysis, we demonstrate that the suppression of CTCF alters cellular plasticity, strengthening the epithelial phenotype via the upregulation of epithelial markers E-cadherin/CDH1 and downregulation of N-cadherin/CDH2. Conversely, the upregulation of CTCF leads to the upregulation of EMT gene expression and an increase in mesenchymal traits. These findings are indicative of a role of CTCF in regulating epithelial–mesenchymal plasticity and gene expression. Full article
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19 pages, 2792 KiB  
Article
Single-Cell RNA-Seq Analysis Reveals the Acquisition of Cancer Stem Cell Traits and Increase of Cell–Cell Signaling during EMT Progression
by Federico Bocci, Peijie Zhou and Qing Nie
Cancers 2021, 13(22), 5726; https://doi.org/10.3390/cancers13225726 - 16 Nov 2021
Cited by 12 | Viewed by 4545
Abstract
Intermediate cell states (ICSs) during the epithelial–mesenchymal transition (EMT) are emerging as a driving force of cancer invasion and metastasis. ICSs typically exhibit hybrid epithelial/mesenchymal characteristics as well as cancer stem cell (CSC) traits including proliferation and drug resistance. Here, we analyze several [...] Read more.
Intermediate cell states (ICSs) during the epithelial–mesenchymal transition (EMT) are emerging as a driving force of cancer invasion and metastasis. ICSs typically exhibit hybrid epithelial/mesenchymal characteristics as well as cancer stem cell (CSC) traits including proliferation and drug resistance. Here, we analyze several single-cell RNA-seq (scRNA-seq) datasets to investigate the relation between several axes of cancer progression including EMT, CSC traits, and cell–cell signaling. To accomplish this task, we integrate computational methods for clustering and trajectory inference with analysis of EMT gene signatures, CSC markers, and cell–cell signaling pathways, and highlight conserved and specific processes across the datasets. Our analysis reveals that “standard” measures of pluripotency often used in developmental contexts do not necessarily correlate with EMT progression and expression of CSC-related markers. Conversely, an EMT circuit energy that quantifies the co-expression of epithelial and mesenchymal genes consistently increases along EMT trajectories across different cancer types and anatomical locations. Moreover, despite the high context specificity of signal transduction across different cell types, cells undergoing EMT always increased their potential to send and receive signals from other cells. Full article
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18 pages, 2428 KiB  
Article
KLF4 Induces Mesenchymal–Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors
by Ayalur Raghu Subbalakshmi, Sarthak Sahoo, Isabelle McMullen, Aaditya Narayan Saxena, Sudhanva Kalasapura Venugopal, Jason A. Somarelli and Mohit Kumar Jolly
Cancers 2021, 13(20), 5135; https://doi.org/10.3390/cancers13205135 - 13 Oct 2021
Cited by 19 | Viewed by 3688
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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27 pages, 6251 KiB  
Article
Identifying Molecular Signatures of Distinct Modes of Collective Migration in Response to the Microenvironment Using Three-Dimensional Breast Cancer Models
by Diana Catalina Ardila, Vaishali Aggarwal, Manjulata Singh, Ansuman Chattopadhyay, Srilakshmi Chaparala and Shilpa Sant
Cancers 2021, 13(6), 1429; https://doi.org/10.3390/cancers13061429 - 20 Mar 2021
Cited by 5 | Viewed by 4127
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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13 pages, 930 KiB  
Review
Quantifying the Epithelial-to-Mesenchymal Transition (EMT) from Bench to Bedside
by Meredith S. Brown, Kristen E. Muller and Diwakar R. Pattabiraman
Cancers 2022, 14(5), 1138; https://doi.org/10.3390/cancers14051138 - 23 Feb 2022
Cited by 13 | Viewed by 3442
Abstract
The epithelial-to-mesenchymal transition (EMT) and its reversal, the mesenchymal-to-epithelial transition (MET) are critical components of the metastatic cascade in breast cancer and many other solid tumor types. Recent work has uncovered the presence of a variety of states encompassed within the EMT spectrum, [...] Read more.
The epithelial-to-mesenchymal transition (EMT) and its reversal, the mesenchymal-to-epithelial transition (MET) are critical components of the metastatic cascade in breast cancer and many other solid tumor types. Recent work has uncovered the presence of a variety of states encompassed within the EMT spectrum, each of which may play unique roles or work collectively to impact tumor progression. However, defining EMT status is not routinely carried out to determine patient prognosis or dictate therapeutic decision-making in the clinic. Identifying and quantifying the presence of various EMT states within a tumor is a critical first step to scoring patient tumors to aid in determining prognosis. Here, we review the major strides taken towards translating our understanding of EMT biology from bench to bedside. We review previously used approaches including basic immunofluorescence staining, flow cytometry, single-cell sequencing, and multiplexed tumor mapping. Future studies will benefit from the consideration of multiple methods and combinations of markers in designing a diagnostic tool for detecting and measuring EMT in patient tumors. Full article
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22 pages, 1084 KiB  
Review
Lineage Plasticity in Cancer: The Tale of a Skin-Walker
by Archana P. Thankamony, Ayalur Raghu Subbalakshmi, Mohit Kumar Jolly and Radhika Nair
Cancers 2021, 13(14), 3602; https://doi.org/10.3390/cancers13143602 - 18 Jul 2021
Cited by 12 | Viewed by 4703
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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20 pages, 1102 KiB  
Review
Phenotypic Heterogeneity of Triple-Negative Breast Cancer Mediated by Epithelial–Mesenchymal Plasticity
by Barbora Kvokačková, Ján Remšík, Mohit Kumar Jolly and Karel Souček
Cancers 2021, 13(9), 2188; https://doi.org/10.3390/cancers13092188 - 2 May 2021
Cited by 36 | Viewed by 5191
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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10 pages, 1434 KiB  
Review
Epithelial–Mesenchymal Transition in Liver Fluke-Induced Cholangiocarcinoma
by Kanlayanee Sawanyawisuth, Goro Sashida and Guojun Sheng
Cancers 2021, 13(4), 791; https://doi.org/10.3390/cancers13040791 - 14 Feb 2021
Cited by 5 | Viewed by 3048
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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