Image quantification technique reveals novel lung cancer cytoskeletal phenotype with partial EMT signature

Epithelial-mesenchymal Transition (EMT) is a multi-step process that involves cytoskeletal rearrangement. Here, using novel image quantification tools, we have identified an intermediate EMT state with a specific cytoskeletal signature. We have been able to partition EMT into two steps: (1) initial formation of transverse arcs and dorsal stress fibers and (2) their subsequent conversion to ventral stress fibers with a concurrent alignment of fibers. Using the Orientational Order Parameter (OOP) as a figure of merit, we have been able to track EMT progression in live cells as well as characterize and quantify drug responses. Our technique has improved throughput and is non-destructive, making it a viable candidate for studying a broad range of biological processes. Further, owing to the increased stiffness (and hence invasiveness) of the intermediate phenotype compared to mesenchymal cells, our work can be instrumental in aiding the search for new treatment strategies that combat metastasis by specifically targeting the fiber alignment process.

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Claudins and Gastric Cancer: An Overview

Cancers ◽

10.3390/cancers14020290 ◽

2022 ◽

Vol 14 (2) ◽

pp. 290

Author(s):

Itaru Hashimoto ◽

Takashi Oshima

Keyword(s):

Gastric Cancer ◽

Cell Adhesion ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Treatment Strategies ◽

The Cancer Genome Atlas ◽

Therapeutic Drug ◽

Mesenchymal Transition ◽

New Treatment ◽

Cell Cell

Despite recent improvements in diagnostic ability and treatment strategies, advanced gastric cancer (GC) has a high frequency of recurrence and metastasis, with poor prognosis. To improve the treatment results of GC, the search for new treatment targets from proteins related to epithelial–mesenchymal transition (EMT) and cell–cell adhesion is currently being conducted. EMT plays an important role in cancer metastasis and is initiated by the loss of cell–cell adhesion, such as tight junctions (TJs), adherens junctions, desmosomes, and gap junctions. Among these, claudins (CLDNs) are highly expressed in some cancers, including GC. Abnormal expression of CLDN1, CLDN2, CLDN3, CLDN4, CLDN6, CLDN7, CLDN10, CLDN11, CLDN14, CLDN17, CLDN18, and CLDN23 have been reported. Among these, CLDN18 is of particular interest. In The Cancer Genome Atlas, GC was classified into four new molecular subtypes, and CLDN18–ARHGAP fusion was observed in the genomically stable type. An anti-CLDN18.2 antibody drug was recently developed as a therapeutic drug for GC, and the results of clinical trials are highly predictable. Thus, CLDNs are highly expressed in GC as TJs and are expected targets for new antibody drugs. Herein, we review the literature on CLDNs, focusing on CLDN18 in GC.

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MiRNA, a New Treatment Strategy for Pulmonary Fibrosis

Current Drug Targets ◽

10.2174/1874609813666200928141822 ◽

2020 ◽

Vol 21 ◽

Author(s):

Yanhong Liu ◽

Hongguang Nie ◽

Yan Ding ◽

Yapeng Hou ◽

Kejun Mao ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Alveolar Epithelial Cell ◽

The Elderly ◽

Matrix Remodeling ◽

Mesenchymal Transition ◽

Delay In Diagnosis ◽

Alveolar Epithelial ◽

Epithelial Cell Apoptosis ◽

New Treatment

: Pulmonary fibrosis (PF) is the most common chronic, progressive interstitial lung disease, mainly occurring in the elderly, with a median survival of 2-4 years after diagnosis. Its high mortality rate attributes to the delay in diagnosis due to its generic symptoms, and more importantly, to the lack of effective treatments. MicroRNAs (miRNAs) are a class of small non-coding RNAs that involve in many essential cellular processes, including extracellular matrix remodeling, alveolar epithelial cell apoptosis, epithelial-mesenchymal transition, etc. We summarized the dysregulated miRNAs in TGF-β signaling pathway-mediated PF in recent years with dual effects, such as anti-fibrotic let-7 family and pro-fibrotic miR-21 members. Therefore, this review will set out the latest application of miRNAs to provide a new direction for PF treatment.

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Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset

Cancers ◽

10.3390/cancers11040483 ◽

2019 ◽

Vol 11 (4) ◽

pp. 483 ◽

Cited By ~ 37

Author(s):

Chiara Agnoletto ◽

Fabio Corrà ◽

Linda Minotti ◽

Federica Baldassari ◽

Francesca Crudele ◽

...

Keyword(s):

Tumor Cells ◽

Circulating Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Cell Subset ◽

Intermediate Phenotype ◽

Current Evidence ◽

Early Event ◽

Tumor Type ◽

Mesenchymal Transition ◽

Immunodeficient Mice

The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial–mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.

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Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

Cells ◽

10.3390/cells9041055 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1055 ◽

Cited By ~ 11

Author(s):

Jacek Baj ◽

Izabela Korona-Głowniak ◽

Alicja Forma ◽

Amr Maani ◽

Elżbieta Sitarz ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Epithelial Mesenchymal Transition ◽

Treatment Strategies ◽

Gastric Ulcers ◽

Heparin Binding ◽

Human Pathogens ◽

Mesenchymal Transition ◽

Cytotoxin Associated Gene A ◽

H Pylori

Helicobacter pylori (H. pylori) is one of the most common human pathogens, affecting half of the world’s population. Approximately 20% of the infected patients develop gastric ulcers or neoplastic changes in the gastric stroma. An infection also leads to the progression of epithelial–mesenchymal transition within gastric tissue, increasing the probability of gastric cancer development. This paper aims to review the role of H. pylori and its virulence factors in epithelial–mesenchymal transition associated with malignant transformation within the gastric stroma. The reviewed factors included: CagA (cytotoxin-associated gene A) along with induction of cancer stem-cell properties and interaction with YAP (Yes-associated protein pathway), tumor necrosis factor α-inducing protein, Lpp20 lipoprotein, Afadin protein, penicillin-binding protein 1A, microRNA-29a-3p, programmed cell death protein 4, lysosomal-associated protein transmembrane 4β, cancer-associated fibroblasts, heparin-binding epidermal growth factor (HB-EGF), matrix metalloproteinase-7 (MMP-7), and cancer stem cells (CSCs). The review summarizes the most recent findings, providing insight into potential molecular targets and new treatment strategies for gastric cancer.

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NACC1, as a Target of MicroRNA-331-3p, Regulates Cell Proliferation in Urothelial Carcinoma Cells

Cancers ◽

10.3390/cancers10100347 ◽

2018 ◽

Vol 10 (10) ◽

pp. 347 ◽

Cited By ~ 8

Author(s):

Kohei Morita ◽

Tomomi Fujii ◽

Hiroe Itami ◽

Tomoko Uchiyama ◽

Tokiko Nakai ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Migration ◽

Urothelial Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Treatment Strategies ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Cell Migration And Invasion ◽

Target Molecule ◽

Target Molecules

The nucleus accumbens-associated protein 1 (NACC1) is a transcription factor constitutively expressed in the urothelium, where it regulates cell growth, senescence, autophagy, and epithelial-mesenchymal transition. microRNA (miRNA) constitutes a class of small non-coding RNAs which are involved in cell proliferation, differentiation, and progression of tumors. miRNAs and their target molecules are utilized for molecular diagnosis of urothelial carcinoma. NACC1 is one of several putative target molecules of miR-331-3p, and is associated with cell proliferation in cancers such as prostate and cervical cancer. Functional experiments involving miR-331-3p and its target molecule NACC1 were conducted using the urothelial carcinoma (UC) cell lines, T24, UMUC6, and KU7. Furthermore, quantitative reverse transcription polymerase chain reaction and immunostaining were performed to evaluate the expression of NACC1 in UC derived from transurethral resection of bladder tumor (TUR-Bt) specimens. The methane thiosulfonate (MTS) assay revealed that cell proliferation was significantly reduced after transient transfection of miR-331-3p precursor and/or NACC1 siRNA in UC cells. Cell senescence via cell cycle arrest at the G1 phase was induced by NACC1 inhibition. On the other hand, suppression of NACC1 induced cell migration and invasion abilities. Immunohistochemical analysis of TUR-Bt specimens revealed that over 70% of UC cells presented strongly positive results for NACC1. In contrast, normal urothelial cells were weakly positive for NACC1. It was also found that NACC1 expression was lower in invasive UC cells than in non-invasive UC cells. Loss of NACC1 induced vessel invasion in invasive UC tissues. The present results indicate that NACC1 regulated by miR-331-3p contributes to cell proliferation, and is involved in cell migration and invasion. This suggests that NACC1 can serve as a potential target molecule for the prediction and prognosis of UC, and can contribute to effective treatment strategies.

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Mechanisms of Invasion in Head and Neck Cancer

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2014-0498-ra ◽

2015 ◽

Vol 139 (11) ◽

pp. 1334-1348 ◽

Cited By ~ 29

Author(s):

Lizandra Jimenez ◽

Sangeeta K. Jayakar ◽

Thomas J. Ow ◽

Jeffrey E. Segall

Keyword(s):

Head And Neck ◽

Locoregional Recurrence ◽

Epithelial Mesenchymal Transition ◽

Advanced Disease ◽

Mesenchymal Transition ◽

Surface Receptors ◽

Node Metastasis ◽

Rate Of Spread ◽

Key Factor ◽

New Treatment

Context The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5-year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed. Objectives To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion. Data Sources A literature review of peer-reviewed articles in PubMed on HNSCC invasion. Conclusions Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation.

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Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia

Nature Communications ◽

10.1038/s41467-021-25403-y ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Johannes Bloehdorn ◽

Andrejs Braun ◽

Amaro Taylor-Weiner ◽

Billy Michael Chelliah Jebaraj ◽

Sandra Robrecht ◽

...

Keyword(s):

Dna Damage ◽

Chronic Lymphocytic Leukemia ◽

Epithelial Mesenchymal Transition ◽

Cytidine Deaminase ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Wild Type ◽

Mesenchymal Transition ◽

Genomic Landscape ◽

New Treatment

AbstractKnowledge of the genomic landscape of chronic lymphocytic leukemia (CLL) grows increasingly detailed, providing challenges in contextualizing the accumulated information. To define the underlying networks, we here perform a multi-platform molecular characterization. We identify major subgroups characterized by genomic instability (GI) or activation of epithelial-mesenchymal-transition (EMT)-like programs, which subdivide into non-inflammatory and inflammatory subtypes. GI CLL exhibit disruption of genome integrity, DNA-damage response and are associated with mutagenesis mediated through activation-induced cytidine deaminase or defective mismatch repair. TP53 wild-type and mutated/deleted cases constitute a transcriptionally uniform entity in GI CLL and show similarly poor progression-free survival at relapse. EMT-like CLL exhibit high genomic stability, reduced benefit from the addition of rituximab and EMT-like differentiation is inhibited by induction of DNA damage. This work extends the perspective on CLL biology and risk categories in TP53 wild-type CLL. Furthermore, molecular targets identified within each subgroup provide opportunities for new treatment approaches.

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In vivo collective cell migration requires an LPAR2-dependent increase in tissue fluidity

The Journal of Cell Biology ◽

10.1083/jcb.201402093 ◽

2014 ◽

Vol 206 (1) ◽

pp. 113-127 ◽

Cited By ~ 80

Author(s):

Sei Kuriyama ◽

Eric Theveneau ◽

Alexandre Benedetto ◽

Maddy Parsons ◽

Masamitsu Tanaka ◽

...

Keyword(s):

Cell Migration ◽

Epithelial Mesenchymal Transition ◽

Intermediate Phenotype ◽

Collective Cell Migration ◽

Embryonic Cells ◽

Lpa Receptor ◽

Mesenchymal Transition ◽

Physical Constraints ◽

Cell Cell

Collective cell migration (CCM) and epithelial–mesenchymal transition (EMT) are common to cancer and morphogenesis, and are often considered to be mutually exclusive in spite of the fact that many cancer and embryonic cells that have gone through EMT still cooperate to migrate collectively. Here we use neural crest (NC) cells to address the question of how cells that have down-regulated cell–cell adhesions can migrate collectively. NC cell dissociation relies on a qualitative and quantitative change of the cadherin repertoire. We found that the level of cell–cell adhesion is precisely regulated by internalization of N-cadherin downstream of lysophosphatidic acid (LPA) receptor 2. Rather than promoting the generation of single, fully mesenchymal cells, this reduction of membrane N-cadherin only triggers a partial mesenchymal phenotype. This intermediate phenotype is characterized by an increase in tissue fluidity akin to a solid-like–to–fluid-like transition. This change of plasticity allows cells to migrate under physical constraints without abolishing cell cooperation required for collectiveness.

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Effect of Huaier on Melanoma Invasion, Metastasis, and Angiogenesis

BioMed Research International ◽

10.1155/2020/8163839 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Dongqiang Su ◽

Bingbing Jiang ◽

Yun Yang ◽

Yu Miao ◽

Qian Fu ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Hypoxia Inducible Factor ◽

Treatment Strategies ◽

Scientific Basis ◽

Comprehensive Treatment ◽

Melanoma Metastasis ◽

Mesenchymal Transition ◽

A375 Cells

Malignant melanoma (MM) is a highly metastatic and malignant cancer. Developing potential drugs with good efficacy and low toxicity for MM treatment is needed. Huaier, extracted from the mushroom Trametes robiniophila Murr, has been widely used in clinical anticancer treatments in China. A previous work done by our group confirmed that Huaier could inhibit cell proliferation and induce apoptosis in human melanoma cells. The current study is aimed at investigating the effects of Huaier on melanoma metastasis and angiogenesis in vitro and in vivo and to explore its possible mechanism of action. Our results showed that Huaier not only significantly inhibited the metastasis of A375 cells at the concentration ranging from 4 to 16 mg/ml (P<0.05), which were determined by the wound healing assay and transwell assay in vitro, but also suppressed the MM tumor growth and metastatic cells to the liver in A375-bearing mice after oral administration at the dose of 5 mg/kg (P<0.05). In addition, Huaier treatment downregulated the expression of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), astrocyte-elevated gene-1 (AEG-1), and N-cadherin, while it upregulated E-cadherin expression in both the A375 cells and tumor tissues, which was detected using western blotting and RT-PCR (P<0.05). Taken together, our data suggests that the antitumor and antimetastatic activities of Huaier are caused by the downregulation of the HIF-1α/VEGF and AEG-1 signaling pathways and by the inhibition of epithelial-mesenchymal transition (EMT). This study provides a new insight into the mechanism of Huaier on antimetastatic therapy and a new scientific basis for comprehensive treatment strategies for MM.

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The Epithelial to Mesenchymal Transition Promotes Glutamine Independence by Suppressing GLS2 Expression

Cancers ◽

10.3390/cancers11101610 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1610 ◽

Cited By ~ 8

Author(s):

Esmeralda Ramirez-Peña ◽

James Arnold ◽

Vinita Shivakumar ◽

Robiya Joseph ◽

Geraldine Vidhya Vijay ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Treatment Strategies ◽

Mitochondrial Activity ◽

Breast Cancer Patients ◽

Mesenchymal Transition ◽

Metabolic Activities ◽

New Treatment

Identifying bioenergetics that facilitate the epithelial to mesenchymal transition (EMT) in breast cancer cells may uncover targets to treat incurable metastatic disease. Metastasis is the number one cause of cancer-related deaths; therefore, it is urgent to identify new treatment strategies to prevent the initiation of metastasis. To characterize the bioenergetics of EMT, we compared metabolic activities and gene expression in cells induced to differentiate into the mesenchymal state with their epithelial counterparts. We found that levels of GLS2, which encodes a glutaminase, are inversely associated with EMT. GLS2 down-regulation was correlated with reduced mitochondrial activity and glutamine independence even in low-glucose conditions. Restoration of GLS2 expression in GLS2-negative breast cancer cells rescued mitochondrial activity, enhanced glutamine utilization, and inhibited stem-cell properties. Additionally, inhibition of expression of the transcription factor FOXC2, a critical regulator of EMT in GLS2-negative cells, restored GLS2 expression and glutamine utilization. Furthermore, in breast cancer patients, high GLS2 expression is associated with improved survival. These findings suggest that epithelial cancer cells rely on glutamine and that cells induced to undergo EMT become glutamine independent. Moreover, the inhibition of EMT leads to a GLS2-directed metabolic shift in mesenchymal cancer cells, which may make these cells susceptible to chemotherapies.

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