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      Metabolism addiction in pancreatic cancer

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          Abstract

          Pancreatic ductal adenocarcinoma, an aggressively invasive, treatment-resistant malignancy and the fourth leading cause of cancer deaths in the United States, is usually detectable only when already inevitably fatal. Despite advances in genetic screening, mapping and molecular characterization, its pathology remains largely elusive. Renewed research interest in longstanding doctrines of tumor metabolism has led to the emergence of aberrant signaling pathways as critical factors modulating central metabolic networks that fuel pancreatic tumors. Such pathways, including those of Ras signaling, glutamine-regulatory enzymes, lipid metabolism and autophagy, are directly affected by genetic mutations and extreme tumor microenvironments that typify pancreatic tumor cells. Elucidation of these metabolic networks can be expected to yield more potent therapies against this deadly disease.

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          On the origin of cancer cells.

          O WARBURG (1956)
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            Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism

            Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC. Copyright © 2012 Elsevier Inc. All rights reserved.
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              Pancreatic cancers require autophagy for tumor growth.

              Macroautophagy (autophagy) is a regulated catabolic pathway to degrade cellular organelles and macromolecules. The role of autophagy in cancer is complex and may differ depending on tumor type or context. Here we show that pancreatic cancers have a distinct dependence on autophagy. Pancreatic cancer primary tumors and cell lines show elevated autophagy under basal conditions. Genetic or pharmacologic inhibition of autophagy leads to increased reactive oxygen species, elevated DNA damage, and a metabolic defect leading to decreased mitochondrial oxidative phosphorylation. Together, these ultimately result in significant growth suppression of pancreatic cancer cells in vitro. Most importantly, inhibition of autophagy by genetic means or chloroquine treatment leads to robust tumor regression and prolonged survival in pancreatic cancer xenografts and genetic mouse models. These results suggest that, unlike in other cancers where autophagy inhibition may synergize with chemotherapy or targeted agents by preventing the up-regulation of autophagy as a reactive survival mechanism, autophagy is actually required for tumorigenic growth of pancreatic cancers de novo, and drugs that inactivate this process may have a unique clinical utility in treating pancreatic cancers and other malignancies with a similar dependence on autophagy. As chloroquine and its derivatives are potent inhibitors of autophagy and have been used safely in human patients for decades for a variety of purposes, these results are immediately translatable to the treatment of pancreatic cancer patients, and provide a much needed, novel vantage point of attack.
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                Author and article information

                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group
                2041-4889
                February 2014
                20 February 2014
                1 February 2014
                : 5
                : 2
                : e1065
                Affiliations
                [1 ]Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine , New York, NY, USA
                [2 ]Department of Neurobiology, Tel Aviv University , Tel Aviv, Israel
                Author notes
                [* ]Department of Pathology and Cancer Institute, Smilow Research Center, New York University School of Medicine , 522 1st Avenue, New York, NY 10016, USA. Tel: +1 972 3 640 9699; Fax: +1 972 3 640 7643; E-mail: blumroy@ 123456gmail.com
                Article
                cddis201438
                10.1038/cddis.2014.38
                3944253
                24556680
                d5ac09d4-3dda-4403-8713-13b3d437c238
                Copyright © 2014 Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 13 November 2013
                : 06 January 2014
                : 08 January 2014
                Categories
                Review

                Cell biology
                pancreatic cancer,oncogenic ras,metabolism,glutamine metabolism,glycolysis,pentose phosphate pathway

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