Adapted suspension tumor cells rewire metabolic pathways for anchorage-independent survival through AKT activation

Abstract BACKGROUND Glioma associated myeloid cells (GAMs) can be induced to adopt an immunosuppressive phenotype that can lead to inhibition of anti-tumor responses in glioblastoma (GBM). Understanding the composition and phenotypes of GAMs is essential to modulating the myeloid compartment as a therapeutic adjunct to improve anti-tumor immune response. METHODS We performed single-cell RNA-sequencing (sc-RNAseq) of 435,400 myeloid and tumor cells to identify transcriptomic and phenotypic differences in GAMs across glioma grades. We further correlated the heterogeneity of the GAM landscape with tumor cell transcriptomics to investigate interactions between GAMs and tumor cells. RESULTS sc-RNAseq revealed a diverse landscape of myeloid-lineage cells in gliomas with an increase in preponderance of bone marrow derived myeloid cells (BMDMs) with increasing tumor grade. We identified two populations of BMDMs unique to GBMs; Mac-1and Mac-2. Mac-1 demonstrates upregulation of immature myeloid gene signature and altered metabolic pathways. Mac-2 is characterized by expression of scavenger receptor MARCO. Pseudotime and RNA velocity analysis revealed the ability of Mac-1 to transition and differentiate to Mac-2 and other GAM subtypes. We further found that the presence of these two populations of BMDMs are associated with the presence of tumor cells with stem cell and mesenchymal features. Bulk RNA-sequencing data demonstrates that gene signatures of these populations are associated with worse survival in GBM. CONCLUSION We used sc-RNAseq to identify a novel population of immature BMDMs that is associated with higher glioma grades. This population exhibited altered metabolic pathways and stem-like potentials to differentiate into other GAM populations including GAMs with upregulation of immunosuppressive pathways. Our results elucidate unique interactions between BMDMs and GBM tumor cells that potentially drives GBM progression and the more aggressive mesenchymal subtype. Our discovery of these novel BMDMs have implications in new therapeutic targets in improving the efficacy of immune-based therapies in GBM.

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Metabolic pathways in Ehrlich ascites tumor cells recovering from a low bioenergetic status

FEBS Letters ◽

10.1016/0014-5793(94)00759-4 ◽

1994 ◽

Vol 350 (2-3) ◽

pp. 183-186 ◽

Cited By ~ 5

Author(s):

Paolo Dell'Antone

Keyword(s):

Tumor Cells ◽

Metabolic Pathways ◽

Ehrlich Ascites Tumor ◽

Ehrlich Ascites Tumor Cells ◽

Ascites Tumor ◽

Ehrlich Ascites

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Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism

Clinical Chemistry ◽

10.1373/clinchem.2018.299651 ◽

2019 ◽

Vol 65 (9) ◽

pp. 1090-1101 ◽

Cited By ~ 17

Author(s):

Sugarniya Subramaniam ◽

Varinder Jeet ◽

Judith A Clements ◽

Jennifer H Gunter ◽

Jyotsna Batra

Keyword(s):

Fatty Acid ◽

Signaling Pathways ◽

Tumor Cells ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Novel Therapeutic

AbstractBACKGROUNDMetabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.CONTENTmiRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.SUMMARYIn this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.

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Tumor Cells and Cancer-Associated Fibroblasts: An Updated Metabolic Perspective

Cancers ◽

10.3390/cancers13030399 ◽

2021 ◽

Vol 13 (3) ◽

pp. 399

Author(s):

Géraldine Gentric ◽

Fatima Mechta-Grigoriou

Keyword(s):

Tumor Cells ◽

Metabolic Pathways ◽

Molecular Mechanisms ◽

Carbon Sources ◽

Cancer Associated Fibroblasts ◽

The Past ◽

Cancer Field ◽

Metabolic Heterogeneity ◽

The Impact ◽

Shed Light

During the past decades, metabolism and redox imbalance have gained considerable attention in the cancer field. In addition to the well-known Warburg effect occurring in tumor cells, numerous other metabolic deregulations have now been reported. Indeed, metabolic reprograming in cancer is much more heterogeneous than initially thought. In particular, a high diversity of carbon sources used by tumor cells has now been shown to contribute to this metabolic heterogeneity in cancer. Moreover, the molecular mechanisms newly highlighted are multiple and shed light on novel actors. Furthermore, the impact of this metabolic heterogeneity on tumor microenvironment has also been an intense subject of research recently. Here, we will describe the new metabolic pathways newly uncovered in tumor cells. We will also have a particular focus on Cancer-Associated Fibroblasts (CAF), whose identity, function and metabolism have been recently under profound investigation. In that sense, we will discuss about the metabolic crosstalk between tumor cells and CAF.

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The Effects of CD82 Palmitoylation on the Metabolic Pathways of EGFR and c-Met in Breast Cancer Cells and their Molecular Mechanisms

10.21203/rs.3.rs-532321/v1 ◽

2021 ◽

Author(s):

Jingya Bu ◽

Weiliang Zhong ◽

Meixian Li ◽

Shuiqing He ◽

Mingzhe Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Membrane ◽

Cancer Cells ◽

Tumor Cells ◽

Metabolic Pathways ◽

Breast Cancer Cells ◽

Molecular Mechanisms ◽

Metastasis Suppressor ◽

Recycling Endosome ◽

Palmitoylation Site

Abstract Background: As a tumor metastasis suppressor, tetraspanin CD82 is reduced in many malignant tumors and often affects the composition of tumor microenvironment by changing the heterogeneity of cell membrane. EGFR or c-Met signaling pathway can regulate the metastasis ability of tumor cells and participate in the formation of tetraspanin web. The study of CD82 palmitoylation modification and metabolic pathway of tumor related molecules in tumor cells is still incomplete. This article focuses on studying the expression and distribution of EGFR and c-Met in cancer cells as well as related metabolic pathways and their molecular mechanisms after studying different palmitoylation site mutations.Methods: Western blot and immunofluorescence methods were used to detect the distribution of EGFR in breast cancer MDA-MB-231 cells after different CD82 palmitoylation site mutations. Then use the immunoprecipitation method to determine the interaction relationship between the molecules and the molecular mechanism.Results: We found that when CD82 combined with palmitoylation mutation at Cys5+Cys74 can enhance the internalization of EGFR, but has no effect on the expression and location of c-Met. When CD82 is combined with palmitoylation mutation at the Cys5+Cys74 site, with the assistance of tubulin, EGFR is internalized and strengthened by direct binding to CD82 and a large number of localizations on the recycling endosome. By forming the EGFR/CD82/Rab11a/FIP2 complex, it is metabolized through the circulation pathway, and re-expression of EGFR and CD82 on the cell membrane.Conclusions: From our results, we can demonatrate that CD82 palmitoylation mutation can change the distribution of EGFR in breast cancer cells, which may provide new ideas for breast cancer treatment.

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Current Progress and Perspectives on Using Gold Compounds for the Modulation of Tumor Cell Metabolism

Frontiers in Chemistry ◽

10.3389/fchem.2021.733463 ◽

2021 ◽

Vol 9 ◽

Author(s):

Leiya Kou ◽

Shuang Wei ◽

Pei Kou

Keyword(s):

Nucleic Acid ◽

Tumor Cells ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Aerobic Glycolysis ◽

Cell Metabolism ◽

Nucleic Acid Metabolism ◽

Metabolic Pattern ◽

Growth And Survival ◽

Gold Compounds

Altered cellular metabolism, which is essential for the growth and survival of tumor cells in a specific microenvironment, is one of the hallmarks of cancer. Among the most significant changes in the metabolic pattern of tumor cells is the shift from oxidative phosphorylation to aerobic glycolysis for glucose utilization. Tumor cells also exhibit changes in patterns of protein and nucleic acid metabolism. Recently, gold compounds have been shown to target several metabolic pathways and a number of metabolites in tumor cells. In this review, we summarize how gold compounds modulate glucose, protein, and nucleic acid metabolism in tumor cells, resulting in anti-tumor effects. We also discuss the rationale underlying the anti-tumor effects of these gold compounds and highlight how to effectively utilize against various types of tumors.

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JC Virus T-Antigen Regulates Glucose Metabolic Pathways in Brain Tumor Cells

PLoS ONE ◽

10.1371/journal.pone.0035054 ◽

2012 ◽

Vol 7 (4) ◽

pp. e35054 ◽

Cited By ~ 14

Author(s):

Evan Noch ◽

Ilker Kudret Sariyer ◽

Jennifer Gordon ◽

Kamel Khalili

Keyword(s):

Brain Tumor ◽

Tumor Cells ◽

Metabolic Pathways ◽

Jc Virus ◽

T Antigen ◽

Brain Tumor Cells

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Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies

Cancers ◽

10.3390/cancers12061668 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1668 ◽

Cited By ~ 3

Author(s):

Monica Mossenta ◽

Davide Busato ◽

Michele Dal Bo ◽

Giuseppe Toffoli

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Cells ◽

Metabolic Pathways ◽

Metabolic Reprogramming ◽

Related Factor ◽

Anti Cancer ◽

Innovative Therapies ◽

Novel Therapeutic Strategies ◽

And Oxidative Stress ◽

Glycolytic Rate

Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid–lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed.

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Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1421601112 ◽

2015 ◽

Vol 112 (8) ◽

pp. 2473-2478 ◽

Cited By ~ 127

Author(s):

Fabienne Guillaumond ◽

Ghislain Bidaut ◽

Mehdi Ouaissi ◽

Stéphane Servais ◽

Victoire Gouirand ◽

...

Keyword(s):

Tumor Cells ◽

Metabolic Pathways ◽

Pancreatic Tumor ◽

Combined Therapy ◽

Disease Patient ◽

Density Lipoprotein ◽

Tumor Stage ◽

Ductal Adenocarcinoma ◽

Cholesterol Uptake ◽

Pancreatic Cancer Cells

The malignant progression of pancreatic ductal adenocarcinoma (PDAC) is accompanied by a profound desmoplasia, which forces proliferating tumor cells to metabolically adapt to this new microenvironment. We established the PDAC metabolic signature to highlight the main activated tumor metabolic pathways. Comparative transcriptomic analysis identified lipid-related metabolic pathways as being the most highly enriched in PDAC, compared with a normal pancreas. Our study revealed that lipoprotein metabolic processes, in particular cholesterol uptake, are drastically activated in the tumor. This process results in an increase in the amount of cholesterol and an overexpression of the low-density lipoprotein receptor (LDLR) in pancreatic tumor cells. These findings identify LDLR as a novel metabolic target to limit PDAC progression. Here, we demonstrate that shRNA silencing of LDLR, in pancreatic tumor cells, profoundly reduces uptake of cholesterol and alters its distribution, decreases tumor cell proliferation, and limits activation of ERK1/2 survival pathway. Moreover, blocking cholesterol uptake sensitizes cells to chemotherapeutic drugs and potentiates the effect of chemotherapy on PDAC regression. Clinically, high PDAC Ldlr expression is not restricted to a specific tumor stage but is correlated to a higher risk of disease recurrence. This study provides a precise overview of lipid metabolic pathways that are disturbed in PDAC. We also highlight the high dependence of pancreatic cancer cells upon cholesterol uptake, and identify LDLR as a promising metabolic target for combined therapy, to limit PDAC progression and disease patient relapse.

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Secreted Protein Acidic, Rich in Cysteine (SPARC), Mediates Cellular Survival of Gliomas through AKT Activation

Journal of Biological Chemistry ◽

10.1074/jbc.m409630200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 52200-52209 ◽

Cited By ~ 88

Author(s):

Qing Shi ◽

Shideng Bao ◽

Jill A. Maxwell ◽

Elizabeth D. Reese ◽

Henry S. Friedman ◽

...

Keyword(s):

Tumor Cells ◽

Matrix Protein ◽

Malignant Gliomas ◽

Dominant Negative ◽

Extracellular Matrix Protein ◽

Secreted Protein ◽

Akt Inhibitor ◽

Akt Phosphorylation ◽

Akt Activation ◽

Sparc Expression

Secreted protein acidic, rich in cysteine (SPARC), is an extracellular matrix protein expressed in many advanced cancers, including malignant gliomas. We and others have previously shown that human glioma cell lines engineered to overexpress SPARC adopt an invasive phenotype. We now show that SPARC expression increases cell survival under stress initiated by serum withdrawal through a decrease in apoptosis. Phosphatidylinositol 3-OH kinase/AKT is a potent pro-survival pathway that contributes to the malignancy of gliomas. Cells expressing SPARC display increased AKT activation with decreased caspase 3/7 activity. Exogenous SPARC rapidly induces AKT phosphorylation, an effect that is blocked by a neutralizing SPARC antibody. Furthermore, AKT activation is essential for the anti-apoptotic effects of SPARC as the decreased apoptosis and caspase activity associated with SPARC expression can be blocked with dominant-negative AKT or a specific AKT inhibitor. As tumor cells face stressful microenvironments particularly during the process of invasion, these results suggest that SPARC functions, in part, to promote tumor progression by enabling tumor cells to survive under stressful conditions.

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