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16 pages, 10993 KiB

Open AccessArticle

Regulation of TGF-β1-Induced EMT by Autophagy-Dependent Energy Metabolism in Cancer Cells

by Jin Seok Hwang, Trang Huyen Lai, Mahmoud Ahmed, Trang Minh Pham, Omar Elashkar, Entaz Bahar and Deok Ryong Kim

Cancers 2022, 14(19), 4845; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194845 - 04 Oct 2022

Cited by 4 | Viewed by 1960

Abstract

Metastasis is associated with poor prognosis and is the major cause of death in cancer patients. The epithelial to mesenchymal transition (EMT) is essential for cancer cells to acquire a highly migratory phenotype. Metabolic reprogramming is required to meet the energy demands during [...] Read more.

Metastasis is associated with poor prognosis and is the major cause of death in cancer patients. The epithelial to mesenchymal transition (EMT) is essential for cancer cells to acquire a highly migratory phenotype. Metabolic reprogramming is required to meet the energy demands during this process. Recent studies have indicated that autophagy is involved in EMT, during which cancer cells depend on autophagy activation for survival. However, accumulating evidence indicates that autophagy’s involvement in cancer is context-dependent, acting as either promoter or inhibitor. In this study, we investigated the role of autophagy in supplying energy to support EMT. We induced EMT in Non-small cell lung cancer A549 cells using TGF-

β

1 with and without autophagy inhibition. Suppression of autophagy activity by knocking down of BECN1 or chloroquine (CQ) treatment inhibited mesenchymal protein expression. Interestingly, TGF-

β

1 promoted the transcription of target mRNAs, SNAI1, VIM, and CDH2, regardless of autophagy status. The imbalance between protein and mRNA levels indicated the possibility of autophagy-dependent translational regulation. Since protein synthesis consumes large amounts of energy, it is tightly regulated via various cellular signaling pathways such as AMPK and mTOR. Our investigation showed inhibition of autophagy decreased ATP production from OXPHOS and led to the suppression of mRNA translation by phosphorylation of eukaryotic elongation factor 2 (eEF2). These results suggest that A549 non-small cell lung cancer required autophagy to maintain mitochondrial homeostasis during TGF-

β

1 induced EMT. In conclusion, blocking autophagy decreased energy production and down-regulated proteins synthesis inhibiting TGF-

β

1 induced EMT. Full article

(This article belongs to the Special Issue EMT in Cancer)

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23 pages, 7051 KiB

Open AccessArticle

NR2F1 Regulates TGF-β1-Mediated Epithelial-Mesenchymal Transition Affecting Platinum Sensitivity and Immune Response in Ovarian Cancer

by Qiuju Liang, Zhijie Xu, Yuanhong Liu, Bi Peng, Yuan Cai, Wei Liu and Yuanliang Yan

Cancers 2022, 14(19), 4639; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194639 - 24 Sep 2022

Cited by 8 | Viewed by 1948

Abstract

The mechanism underlying platinum resistance in ovarian cancer (OC) remains unclear. We used bioinformatic analyses to screen differentially expressed genes responsible for platinum resistance and explore NR2F1′s correlation with prognostic implication and OC staging. Moreover, Gene-set enrichment analysis (GSEA) and Gene Ontology (GO) [...] Read more.

The mechanism underlying platinum resistance in ovarian cancer (OC) remains unclear. We used bioinformatic analyses to screen differentially expressed genes responsible for platinum resistance and explore NR2F1′s correlation with prognostic implication and OC staging. Moreover, Gene-set enrichment analysis (GSEA) and Gene Ontology (GO) analyses were used for pathway analysis. Epithelial-mesenchymal transition (EMT) properties, invasion, and migration capacities were analyzed by biochemical methods. The association between NR2F1 and cancer-associated fibroblast (CAF) infiltration and immunotherapeutic responses were also researched. A total of 13 co-upregulated genes and one co-downregulated gene were obtained. Among them, NR2F1 revealed the highest correlation with a poor prognosis and positively correlated with OC staging. GSEA and GO analysis suggested the induction of EMT via TGFβ-1 might be a possible mechanism that NR2F1 participates in resistance. In vitro experiments showed that NR2F1 knockdown did not affect cell proliferation, but suppressed cell invasion and migration with or without cisplatin treatment through the EMT pathway. We also found that NR2F1 could regulate TGF-β1 signaling, and treating with TGF-β1 could reverse these effects. Additionally, NR2F1 was predominantly associated with immunosuppressive CAF infiltration, which might cause a poor response to immune check blockades. In conclusion, NR2F1 regulates TGF-β1-mediated EMT affecting platinum sensitivity and immune response in OC patients. Full article

(This article belongs to the Special Issue EMT in Cancer)

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18 pages, 2941 KiB

Open AccessArticle

Emergence of Resistance to MTI-101 Selects for a MET Genotype and Phenotype in EGFR Driven PC-9 and PTEN Deleted H446 Lung Cancer Cell Lines

by Clark Jones, Sebastian Dziadowicz, Samuel Suite, Ashley Eby, Wei-Chih Chen, Gangqing Hu and Lori A. Hazlehurst

Cancers 2022, 14(13), 3062; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14133062 - 22 Jun 2022

Cited by 2 | Viewed by 1770

Abstract

MTI-101 is a first-in-class cyclic peptide that kills cells via calcium overload in a caspase-independent manner. Understanding biomarkers of response is critical for positioning a novel therapeutic toward clinical development. Isogenic MTI-101-acquired drug-resistant lung cancer cell line systems (PC-9 and H446) coupled with [...] Read more.

MTI-101 is a first-in-class cyclic peptide that kills cells via calcium overload in a caspase-independent manner. Understanding biomarkers of response is critical for positioning a novel therapeutic toward clinical development. Isogenic MTI-101-acquired drug-resistant lung cancer cell line systems (PC-9 and H446) coupled with differential RNA-SEQ analysis indicated that downregulated genes were enriched in the hallmark gene set for epithelial-to-mesenchymal transition (EMT) in both MTI-101-acquired resistant cell lines. The RNA-SEQ results were consistent with changes in the phenotype, including a decreased invasion in Matrigel and expression changes in EMT markers (E-cadherin, vimentin and Twist) at the protein level. Furthermore, in the EGFR-driven PC-9 cell line, selection for resistance towards MTI-101 resulted in collateral sensitivity toward EGFR inhibitors. MTI-101 treatment showed synergistic activity with the standard of care agents erlotinib, osimertinib and cisplatin when used in combination in PC-9 and H446 cells, respectively. Finally, in vivo data indicate that MTI-101 treatment selects for increased E-cadherin and decreased vimentin in H446, along with a decreased incident of bone metastasis in the PC-9 in vivo model. Together, these data indicate that chronic MTI-101 treatment can lead to a change in cell state that could potentially be leveraged therapeutically to reduce metastatic disease. Full article

(This article belongs to the Special Issue EMT in Cancer)

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18 pages, 2197 KiB

Open AccessFeature PaperArticle

Epithelial-to-Mesenchymal Transition Mediates Resistance to Maintenance Therapy with Vinflunine in Advanced Urothelial Cell Carcinoma

by Albert Font, Vicenç Ruiz de Porras, Begoña P. Valderrama, Jose Luis Ramirez, Lara Nonell, José Antonio Virizuela, Urbano Anido, Aránzazu González-del-Alba, Nuria Lainez, Maria del Mar Llorente, Natalia Jiménez, Begoña Mellado, Jesus García-Donas and Joaquim Bellmunt

Cancers 2021, 13(24), 6235; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13246235 - 12 Dec 2021

Cited by 2 | Viewed by 2879

Abstract

In the phase II MAJA trial, maintenance therapy with vinflunine resulted in longer progression-free survival compared to best supportive care in advanced urothelial cell carcinoma (aUCC) patients who did not progress after first-line platinum-based chemotherapy. However, despite an initial benefit observed in some [...] Read more.

In the phase II MAJA trial, maintenance therapy with vinflunine resulted in longer progression-free survival compared to best supportive care in advanced urothelial cell carcinoma (aUCC) patients who did not progress after first-line platinum-based chemotherapy. However, despite an initial benefit observed in some patients, unequivocal resistance appears which underlying mechanisms are presently unknown. We have performed gene expression and functional enrichment analyses to shed light on the discovery of these underlying resistance mechanisms. Differential gene expression profile of eight patients with poor outcome and nine with good outcome to vinflunine administered in the MAJA trial were analyzed. RNA was isolated from tumor tissue and gene expression was assessed by microarray. Differential expression was determined with linear models for microarray data. Gene Set Enrichment Analysis (GSEA) was used for the functional classification of the genes. In vitro functional studies were performed using UCC cell lines. Hierarchical clustering showed a differential gene expression pattern between patients with good and poor outcome to vinflunine treatment. GSEA identified epithelial-to-mesenchymal transition (EMT) as the top negatively enriched hallmark in patients with good outcome. In vitro analyses showed that the polyphenol curcumin downregulated EMT markers and sensitized UCC cells to vinflunine. We conclude that EMT mediates resistance to vinflunine and suggest that the reversion of this process could enhance the effect of vinflunine in aUCC patients. Full article

(This article belongs to the Special Issue EMT in Cancer)

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Review

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11 pages, 286 KiB

Open AccessReview

Forward Genetic Screens as Tools to Investigate Role and Mechanisms of EMT in Cancer

by Ákos Gasparics and Attila Sebe

Cancers 2022, 14(23), 5928; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235928 - 30 Nov 2022

Cited by 3 | Viewed by 1487

Abstract

Epithelial–mesenchymal transition (EMT) is a process of cellular plasticity regulated by complex signaling networks. Under physiological conditions, it plays an important role in wound healing and organ repair. Its importance for human disease is given by its central role in chronic fibroproliferative diseases [...] Read more.

Epithelial–mesenchymal transition (EMT) is a process of cellular plasticity regulated by complex signaling networks. Under physiological conditions, it plays an important role in wound healing and organ repair. Its importance for human disease is given by its central role in chronic fibroproliferative diseases and cancer, which represent leading causes of death worldwide. In tumors, EMT is involved in primary tumor growth, metastasis and therapy resistance. It is therefore a major requisite to investigate and understand the role of EMT and the mechanisms leading to EMT in order to tackle these diseases therapeutically. Forward genetic screens link genome modifications to phenotypes, and have been successfully employed to identify oncogenes, tumor suppressor genes and genes involved in metastasis or therapy resistance. In particular, transposon-based insertional mutagenesis screens and CRISPR-based screens are versatile and easy-to-use tools applied in recent years to discover and identify novel cancer-related mechanisms. Here, we review the contribution of forward genetic screens to our understanding of how EMT is regulated and how it is involved in various aspects of cancer. Based on the current literature, we propose these methods as additional tools to investigate EMT. Full article

(This article belongs to the Special Issue EMT in Cancer)

23 pages, 804 KiB

Open AccessReview

Implications of Gut Microbiota in Epithelial–Mesenchymal Transition and Cancer Progression: A Concise Review

by Ishita Gupta, Shona Pedersen, Semir Vranic and Ala-Eddin Al Moustafa

Cancers 2022, 14(12), 2964; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122964 - 16 Jun 2022

Cited by 5 | Viewed by 3040

Abstract

Advancement in the development of molecular sequencing platforms has identified infectious bacteria or viruses that trigger the dysregulation of a set of genes inducing the epithelial–mesenchymal transition (EMT) event. EMT is essential for embryogenesis, wound repair, and organ development; meanwhile, during carcinogenesis, initiation [...] Read more.

Advancement in the development of molecular sequencing platforms has identified infectious bacteria or viruses that trigger the dysregulation of a set of genes inducing the epithelial–mesenchymal transition (EMT) event. EMT is essential for embryogenesis, wound repair, and organ development; meanwhile, during carcinogenesis, initiation of the EMT can promote cancer progression and metastasis. Recent studies have reported that interactions between the host and dysbiotic microbiota in different tissues and organs, such as the oral and nasal cavities, esophagus, stomach, gut, skin, and the reproductive tract, may provoke EMT. On the other hand, it is revealed that certain microorganisms display a protective role against cancer growth, indicative of possible therapeutic function. In this review, we summarize recent findings elucidating the underlying mechanisms of pathogenic microorganisms, especially the microbiota, in eliciting crucial regulator genes that induce EMT. Such an approach may help explain cancer progression and pave the way for developing novel preventive and therapeutic strategies. Full article

(This article belongs to the Special Issue EMT in Cancer)

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31 pages, 2677 KiB

Open AccessReview

Glioblastoma Microenvironment and Cellular Interactions

by Carmen-Bianca Crivii, Adina Bianca Boșca, Carmen Stanca Melincovici, Anne-Marie Constantin, Mariana Mărginean, Eleonora Dronca, Rada Suflețel, Diana Gonciar, Maria Bungărdean and Alina Șovrea

Cancers 2022, 14(4), 1092; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14041092 - 21 Feb 2022

Cited by 28 | Viewed by 4334

Abstract

The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this [...] Read more.

The central nervous system (CNS) represents a complex network of different cells, such as neurons, glial cells, and blood vessels. In tumor pathology, glial cells result in the highest number of cancers, and glioblastoma (GB) is considered the most lethal tumor in this region. The development of GB leads to the infiltration of healthy tissue through the interaction between all the elements of the brain network. This results in a GB microenvironment, a complex peritumoral hallo composed of tumor cells and several non-tumor cells (e.g., nervous cells, stem cells, fibroblasts, vascular and immune cells), which might be the principal factor for the ineffective treatment due to the fact that the microenvironment modulates the biologic status of the tumor with the increase in its evasion capacity. Crosstalk between glioma cells and the brain microenvironment finally inhibits the beneficial action of molecular pathways, favoring the development and invasion of the tumor and its increasing resistance to treatment. A deeper understanding of cell–cell interactions in the tumor microenvironment (TME) and with the tumor cells could be the basis for a more efficient therapy. Full article

(This article belongs to the Special Issue EMT in Cancer)

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17 pages, 1049 KiB

Open AccessReview

AXL Receptor in Cancer Metastasis and Drug Resistance: When Normal Functions Go Askew

by Almira Auyez, A. Emre Sayan, Marina Kriajevska and Eugene Tulchinsky

Cancers 2021, 13(19), 4864; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13194864 - 28 Sep 2021

Cited by 20 | Viewed by 4586

Abstract

The TAM proteins TYRO3, AXL, and MER are receptor tyrosine kinases implicated in the clearance of apoptotic debris and negative regulation of innate immune responses. AXL contributes to immunosuppression by terminating the Toll-like receptor signaling in dendritic cells, and suppressing natural killer cell [...] Read more.

The TAM proteins TYRO3, AXL, and MER are receptor tyrosine kinases implicated in the clearance of apoptotic debris and negative regulation of innate immune responses. AXL contributes to immunosuppression by terminating the Toll-like receptor signaling in dendritic cells, and suppressing natural killer cell activity. In recent years, AXL has been intensively studied in the context of cancer. Both molecules, the receptor, and its ligand GAS6, are commonly expressed in cancer cells, as well as stromal and infiltrating immune cells. In cancer cells, the activation of AXL signaling stimulates cell survival and increases migratory and invasive potential. In cells of the tumour microenvironment, AXL pathway potentiates immune evasion. AXL has been broadly implicated in the epithelial-mesenchymal plasticity of cancer cells, a key factor in drug resistance and metastasis. Several antibody-based and small molecule AXL inhibitors have been developed and used in preclinical studies. AXL inhibition in various mouse cancer models reduced metastatic spread and improved the survival of the animals. AXL inhibitors are currently being tested in several clinical trials as monotherapy or in combination with other drugs. Here, we give a brief overview of AXL structure and regulation and discuss the normal physiological functions of TAM receptors, focusing on AXL. We present a theory of how epithelial cancers exploit AXL signaling to resist cytotoxic insults, in order to disseminate and relapse. Full article

(This article belongs to the Special Issue EMT in Cancer)

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