Quantifying the patterns of metabolic plasticity and heterogeneity along the epithelial-hybrid-mesenchymal spectrum in cancer

Cancer metastasis is the leading cause of cancer-related mortality and the process of Epithelial to Mesenchymal Transition (EMT) is crucial for cancer metastasis. Either a partial or complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among oxidative phosphorylation, fatty acid oxidation and glycolysis pathways. However, a comprehensive analysis of these major metabolic pathways their associations with EMT across different cancers is lacking. Here, we analyse more than 180 cancer cell datasets and show diverse associations of these metabolic pathways with the EMT status of cancer cells. Our bulk data analysis shows that EMT generally positively correlates with glycolysis but negatively with oxidative phosphorylation and fatty acid metabolism. These correlations are also consistent at the level of their molecular master regulators, namely AMPK and HIF1α. Yet, these associations are shown to not be universal. Analysis of single-cell data of EMT induction shows dynamic changes along the different axes of metabolic pathways, consistent with general trends seen in bulk samples. Together, our results reveal underlying patterns of metabolic plasticity and heterogeneity as cancer cells traverse through the epithelial-hybrid-mesenchymal spectrum of states.

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Ovalitenone Inhibits the Migration of Lung Cancer Cells via the Suppression of AKT/mTOR and Epithelial-to-Mesenchymal Transition

Molecules ◽

10.3390/molecules26030638 ◽

2021 ◽

Vol 26 (3) ◽

pp. 638

Author(s):

Kittipong Sanookpan ◽

Nongyao Nonpanya ◽

Boonchoo Sritularak ◽

Pithi Chanvorachote

Keyword(s):

Lung Cancer ◽

Cell Migration ◽

Cancer Cells ◽

Colony Formation ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

A549 Cells ◽

Lung Cancer Cells ◽

Migration And Invasion ◽

Mesenchymal Transition

Cancer metastasis is the major cause of about 90% of cancer deaths. As epithelial-to-mesenchymal transition (EMT) is known for potentiating metastasis, this study aimed to elucidate the effect of ovalitenone on the suppression of EMT and metastasis-related behaviors, including cell movement and growth under detached conditions, and cancer stem cells (CSCs), of lung cancer cells. Methods: Cell viability and cell proliferation were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazo-liumbromide (MTT) and colony formation assays. Cell migration and invasion were analyzed using a wound-healing assay and Boyden chamber assay, respectively. Anchorage-independent cell growth was determined. Cell protrusions (filopodia) were detected by phalloidin-rhodamine staining. Cancer stem cell phenotypes were assessed by spheroid formation. The proteins involved in cell migration and EMT were evaluated by Western blot analysis and immunofluorescence staining. Results: Ovalitenone was used at concentrations of 0–200 μM. While it caused no cytotoxic effects on lung cancer H460 and A549 cells, ovalitenone significantly suppressed anchorage-independent growth, CSC-like phenotypes, colony formation, and the ability of the cancer to migrate and invade cells. The anti-migration activity was confirmed by the reduction of filopodia in the cells treated with ovalitenone. Interestingly, we found that ovalitenone could significantly decrease the levels of N-cadherin, snail, and slug, while it increased E-cadherin, indicating EMT suppression. Additionally, the regulatory signaling of focal adhesion kinase (FAK), ATP-dependent tyrosine kinase (AKT), the mammalian target of rapamycin (mTOR), and cell division cycle 42 (Cdc42) was suppressed by ovalitenone. Conclusions: The results suggest that ovalitenone suppresses EMT via suppression of the AKT/mTOR signaling pathway. In addition, ovalitenone exhibited potential for the suppression of CSC phenotypes. These data reveal the anti-metastasis potential of the compound and support the development of ovalitenone treatment for lung cancer therapy.

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Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Cells ◽

10.3390/cells9061539 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1539 ◽

Cited By ~ 2

Author(s):

Peter Ping Lin

Keyword(s):

Endothelial Cells ◽

Tumor Microenvironment ◽

Cancer Cells ◽

Tumor Cells ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Vasculogenic Mimicry ◽

Mesenchymal Transition ◽

Tumor Neovascularization ◽

Hypoxic Tumor

Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.

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Towards Decoding the Metabolic Plasticity in Cancer: Coupling of Gene Regulation and Metabolic Pathways

10.1101/428367 ◽

2018 ◽

Author(s):

Dongya Jia ◽

Mingyang Lu ◽

Kwang Hwa Jung ◽

Jun Hyoung Park ◽

Linglin Yu ◽

...

Keyword(s):

Gene Regulation ◽

Cancer Cells ◽

Metabolic Pathway ◽

Metabolic Pathways ◽

Breast Cancer Cell Lines ◽

Acid Oxidation ◽

Master Regulators ◽

Metabolic Plasticity ◽

Metabolite Abundance

AbstractMetabolic plasticity enables cancer cells to switch their metabolism phenotypes between glycolysis and oxidative phosphorylation (OXPHOS) during tumorigenesis and metastasis. However, it is still largely unknown how cancer cells orchestrate gene regulation to balance their glycolysis and OXPHOS activities for better survival. Here, we establish a theoretical framework to model the coupling of gene regulation and metabolic pathways in cancer. Our modeling results demonstrate a direct association between the activities of AMPK and HIF-1, master regulators of OXPHOS and glycolysis respectively, with the activities of three metabolic pathways: glucose oxidation, glycolysis and fatty acid oxidation (FAO). Guided by the model, we develop metabolic pathway signatures to quantify the activities of glycolysis, FAO and the citric acid cycle of tumor samples by evaluating the expression levels of enzymes involved in corresponding processes. The association of AMPK/HIF-1 activity with metabolic pathway activity, predicted by the model and verified by analyzing the gene expression and metabolite abundance data of patient samples, is further validated by in vitro studies of aggressive triple negative breast cancer cell lines.

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Control of the Epithelial-to-Mesenchymal Transition and Cancer Metastasis by Autophagy-Dependent SNAI1 Degradation

Cells ◽

10.3390/cells8020129 ◽

2019 ◽

Vol 8 (2) ◽

pp. 129 ◽

Cited By ~ 9

Author(s):

Sahib Zada ◽

Jin Hwang ◽

Mahmoud Ahmed ◽

Trang Lai ◽

Trang Pham ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Nuclear Translocation ◽

Degradation Process ◽

Mesenchymal Transition ◽

Invasion And Migration

Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against genotoxic components, leading to cancerous transformation. It can also promote cancer cell survival by supplying minimal amounts of nutrients during cancer progression. However, the molecular mechanisms underlying how autophagy regulates the epithelial-to-mesenchymal transition (EMT) and cancer metastasis are unknown. Here, we show that starvation-induced autophagy promotes Snail (SNAI1) degradation and inhibits EMT and metastasis in cancer cells. Interestingly, SNAI1 proteins were physically associated and colocalized with LC3 and SQSTM1 in cancer cells. We also found a significant decrease in the levels of EMT and metastatic proteins under starvation conditions. Furthermore, ATG7 knockdown inhibited autophagy-induced SNAI1 degradation in the cytoplasm, which was associated with a decrease in SNAI1 nuclear translocation. Moreover, cancer cell invasion and migration were significantly inhibited by starvation-induced autophagy. These findings suggest that autophagy-dependent SNAI1 degradation could specifically regulate EMT and cancer metastasis during tumorigenesis.

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Engineering liver microtissues to study the fusion of HepG2 with mesenchymal stem cells and invasive potential of fused cells

Biofabrication ◽

10.1088/1758-5090/ac36de ◽

2021 ◽

Author(s):

Junmin Lee ◽

Aly Ung ◽

Hanjun Kim ◽

KangJu Lee ◽

Hyun-Jong Cho ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Human Mesenchymal Stem Cells ◽

Hybrid Cells ◽

Invasive Potential ◽

Mesenchymal Transition ◽

Matrix Deposition

Abstract Increasing evidence from cancer cell fusion with different cell types in the tumor microenvironment has suggested a probable mechanism for how metastasis-initiating cells could be generated in tumors. Although human mesenchymal stem cells (hMSCs) have been known as promising candidates to create hybrid cells with cancer cells, the role of hMSCs in fusion with cancer cells is still controversial. Here, we fabricated a liver-on-a-chip platform to monitor the fusion of liver hepatocellular cells (HepG2) with hMSCs and study their invasive potential. We demonstrated that hMSCs might play dual roles in HepG2 spheroids. The analysis of tumor growth with different fractions of hMSCs in HepG2 spheroids revealed hMSCs’ role in preventing HepG2 growth and proliferation, while the hMSCs presented in the HepG2 spheroids led to the generation of HepG2-hMSC hybrid cells with much higher invasiveness compared to HepG2. These invasive HepG2-hMSC hybrid cells expressed high levels of markers associated with stemness, proliferation, epithelial to mesenchymal transition, and matrix deposition, which corresponded to the expression of these markers for hMSCs escaping from hMSC spheroids. In addition, these fused cells were responsible for collective invasion following HepG2 by depositing Collagen I and Fibronectin in their surrounding microenvironment. Furthermore, we showed that hepatic stellate cells (HSCs) could also be fused with HepG2, and the HepG2-HSC hybrid cells possessed similar features to those from HepG2-hMSC fusion. This fusion of HepG2 with liver-resident HSCs may propose a new potential mechanism of hepatic cancer metastasis.

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GSK-3β-mediated fatty acid synthesis enhances epithelial to mesenchymal transition of TLR4-activated colorectal cancer cells through regulation of TAp63

International Journal of Oncology ◽

10.3892/ijo.2016.3679 ◽

2016 ◽

Vol 49 (5) ◽

pp. 2163-2172 ◽

Cited By ~ 8

Author(s):

Ga Bin Park ◽

Yoon Hee Chung ◽

Ji Hee Gong ◽

Dong-Hoon Jin ◽

Daejin Kim

Keyword(s):

Colorectal Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Fatty Acid Synthesis ◽

Epithelial To Mesenchymal Transition ◽

Acid Synthesis ◽

Mesenchymal Transition ◽

Colorectal Cancer Cells ◽

Gsk 3Β

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Epithelial-to-mesenchymal transition involves triacylglycerol accumulation in DU145 prostate cancer cells

Molecular BioSystems ◽

10.1039/c5mb00413f ◽

2015 ◽

Vol 11 (12) ◽

pp. 3397-3406 ◽

Cited By ~ 24

Author(s):

Núria Dalmau ◽

Joaquim Jaumot ◽

Romà Tauler ◽

Carmen Bedia

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Crucial Role ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Biological Process ◽

Prostate Cancer Cells ◽

Mesenchymal Transition ◽

Triacylglycerol Accumulation

Epithelial to mesenchymal transition (EMT) is a biological process that plays a crucial role in cancer metastasis.

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Resveratrol and Its Analogs: Potent Agents to Reverse Epithelial-to-Mesenchymal Transition in Tumors

Frontiers in Oncology ◽

10.3389/fonc.2021.644134 ◽

2021 ◽

Vol 11 ◽

Author(s):

Kaibo Guo ◽

Yuqian Feng ◽

Xueer Zheng ◽

Leitao Sun ◽

Harpreet S. Wasan ◽

...

Keyword(s):

Tumor Microenvironment ◽

Basement Membrane ◽

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Invasion And Metastasis ◽

Mesenchymal Transition ◽

Antiproliferative Effects ◽

Invasion And Migration ◽

And Migration

Epithelial-to-mesenchymal transition (EMT), a complicated program through which polarized epithelial cells acquire motile mesothelial traits, is regulated by tumor microenvironment. EMT is involved in tumor progression, invasion and metastasis via reconstructing the cytoskeleton and degrading the tumor basement membrane. Accumulating evidence shows that resveratrol, as a non-flavonoid polyphenol, can reverse EMT and inhibit invasion and migration of human tumors via diverse mechanisms and signaling pathways. In the present review, we will summarize the detailed mechanisms and pathways by which resveratrol and its analogs (e.g. Triacetyl resveratrol, 3,5,4’-Trimethoxystilbene) might regulate the EMT process in cancer cells to better understand their potential as novel anti-tumor agents. Resveratrol can also reverse chemoresistance via EMT inhibition and improvement of the antiproliferative effects of conventional treatments. Therefore, resveratrol and its analogs have the potential to become novel adjunctive agents to inhibit cancer metastasis, which might be partly related to their blocking of the EMT process.

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Epigenetic Regulation of Epithelial to Mesenchymal Transition in the Cancer Metastatic Cascade: Implications for Cancer Therapy

Frontiers in Oncology ◽

10.3389/fonc.2021.657546 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qiu-Luo Liu ◽

Maochao Luo ◽

Canhua Huang ◽

Hai-Ning Chen ◽

Zong-Guang Zhou

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Epigenetic Regulation ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Metastatic Cascade ◽

Subsequent Transformation ◽

Metastatic Cells

Metastasis is the end stage of cancer progression and the direct cause of most cancer-related deaths. The spreading of cancer cells from the primary site to distant organs is a multistep process known as the metastatic cascade, including local invasion, intravasation, survival in the circulation, extravasation, and colonization. Each of these steps is driven by the acquisition of genetic and/or epigenetic alterations within cancer cells, leading to subsequent transformation of metastatic cells. Epithelial–mesenchymal transition (EMT), a cellular process mediating the conversion of cell from epithelial to mesenchymal phenotype, and its reverse transformation, termed mesenchymal–epithelial transition (MET), together endow metastatic cells with traits needed to generate overt metastases in different scenarios. The dynamic shift between these two phenotypes and their transitional state, termed partial EMT, emphasizes the plasticity of EMT. Recent advances attributed this plasticity to epigenetic regulation, which has implications for the therapeutic targeting of cancer metastasis. In this review, we will discuss the association between epigenetic events and the multifaceted nature of EMT, which may provide insights into the steps of the cancer metastatic cascade.

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