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      Severe metabolic alterations in liver cancer lead to ERK pathway activation and drug resistance

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          The extracellular signal-regulated kinase (ERK) pathway regulates cell growth, and is hyper-activated and associated with drug resistance in hepatocellular carcinoma (HCC). Metabolic pathways are profoundly dysregulated in HCC. Whether an altered metabolic state is linked to activated ERK pathway and drug response in HCC is unaddressed.


          We deprived HCC cells of glutamine to induce metabolic alterations and performed various assays, including metabolomics (with 13C-glucose isotope tracing), microarray analysis, and cell proliferation assays. Glutamine-deprived cells were also treated with kinase inhibitors ( e.g. Sorafenib, Erlotinib, U0126 amongst other MEK inhibitors). We performed bioinformatics analysis and stratification of HCC tumour microarrays to determine upregulated ERK gene signatures in patients.


          In a subset of HCC cells, the withdrawal of glutamine triggers a severe metabolic alteration and ERK phosphorylation (pERK). This is accompanied by resistance to the anti-proliferative effect of kinase inhibitors, despite pERK inhibition. High intracellular serine is a consistent feature of an altered metabolic state and contributes to pERK induction and the kinase inhibitor resistance. Blocking the ERK pathway facilitates cell proliferation by reprogramming metabolism, notably enhancing aerobic glycolysis. We have identified 24 highly expressed ERK gene signatures that their combined expression strongly indicates a dysregulated metabolic gene network in human HCC tissues.


          A severely compromised metabolism lead to ERK pathway induction, and primes some HCC cells to pro-survival phenotypes upon ERK pathway blockade. Our findings offer novel insights for understanding, predicting and overcoming drug resistance in liver cancer patients.


          DFG, BMBF and Sino-German Cooperation Project

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          Most cited references 24

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          Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

          Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.
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            Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis.

            Most tumors exhibit increased glucose metabolism to lactate, however, the extent to which glucose-derived metabolic fluxes are used for alternative processes is poorly understood. Using a metabolomics approach with isotope labeling, we found that in some cancer cells a relatively large amount of glycolytic carbon is diverted into serine and glycine metabolism through phosphoglycerate dehydrogenase (PHGDH). An analysis of human cancers showed that PHGDH is recurrently amplified in a genomic region of focal copy number gain most commonly found in melanoma. Decreasing PHGDH expression impaired proliferation in amplified cell lines. Increased expression was also associated with breast cancer subtypes, and ectopic expression of PHGDH in mammary epithelial cells disrupted acinar morphogenesis and induced other phenotypic alterations that may predispose cells to transformation. Our findings show that the diversion of glycolytic flux into a specific alternate pathway can be selected during tumor development and may contribute to the pathogenesis of human cancer.
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              Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells

              Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using stable isotope-resolved metabolomics. Using [U-(13)C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-(13)C,(15)N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their (13)C-labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency makes them susceptible to the glutaminase inhibitor BPTES and hence could be targeted for cancer therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

                Author and article information

                21 April 2020
                April 2020
                21 April 2020
                : 54
                [a ]Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany
                [b ]Luxembourg Science Center, L-4620 Differdange, Luxembourg, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-Belval, Luxembourg
                [c ]Signal Transduction Laboratory, Life Sciences Research Unit, University of Luxembourg, L-4367 Belvaux, Luxembourg
                [d ]Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, 31527 Tanta, Egypt
                [e ]Department of Medicine I, Lichtenberg Research Group, Johannes Gutenberg University, Mainz, Germany
                [f ]Department of Biology, Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, 69120 Heidelberg, Germany
                [g ]Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, 46556 IN, United States
                [h ]Medical Research Center, Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
                [i ]Rogel Cancer Center, University of Michigan, Ann Arbor 48109 MI, United States
                [j ]Medical Faculty Mannheim, ECAS TRIDOMUS-Gebäude Haus C, University of Heidelberg, 68167 Mannheim, Germany
                [k ]IBCS-BIP, Campus Nord, Karlsruhe Institute for Technology (KIT), 76021 Karlsruhe, Germany
                [l ]Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of Tübingen, 70376 Stuttgart, Germany
                Author notes
                [* ]Current Address of Corresponding author: Department of Molecular and Integrative Physiology, Rogel Cancer Centre, University of Michigan, Ann Arbor, 48109 MI, USA. zcnwosu@ 123456umich.edu
                [# ]Address of the Corresponding/Senior author: Department of Medicine II, Molecular Hepatology Section, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. steven.dooley@ 123456medma.uni-heidelberg.de
                S2352-3964(20)30074-8 102699
                © 2020 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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