Presented by Hot Topics in Life Sciences
Cancer Metabolomics: Elucidating the Biochemical Programs that Support Cancer Initiation and Progression
Posted April 12, 2012
In the early part of the 20th century, German biochemist Otto Warburg observed that tumor tissues and normal tissues metabolize glucose differently. Instead of relying on the citric acid cycle to extract maximal energy from a molecule of glucose, tumor cells rapidly convert glucose to lactate through glycolysis even when oxygen is abundant.
Known as the Warburg effect, this observation sits at the core of the field now known as cancer metabolomics. But for many years after Warburg's observation, scientists focused on separate mechanisms of oncogenesis without considering that these metabolic differences could drive the formation of new cancers or could speed their growth. More recently, cancer researchers have recognized that these metabolic changes help cancer cells build the macromolecules that support the rapid growth and proliferation of tumors.
Organized by Stephen S. Gross of Weill Cornell Medical College and Jennifer Henry of the Academy, the Cancer Metabolomics: Elucidating the Biochemical Programs that Support Cancer Initiation and Progression symposium held on February 3, 2012, is the latest in a series of meetings about cancer metabolomics. In an initial keynote address, Craig Thompson of Memorial Sloan Kettering Cancer Center gave an overview of the field and of the emerging links between oncogenic and metabolic pathways. Gary Siuzdak of Scripps Research Institute described metabolomics tools and the process of finding new cancer metabolites. As one slice of her research on sirtuin enzymes, Marcia Haigis of Harvard Medical School outlined how mitochondrial forms of these enzymes may be involved in cancer growth and proliferation. Joshua Rabinowitz of Princeton University explained fatty acid metabolism in cancer cells, and Eileen White of the Cancer Institute of New Jersey described autophagy in cancer cells. In a second keynote talk, Lewis Cantley of Beth Israel Deaconess Medical Center and Harvard Medical School discussed biochemical research to understand metabolic signals in cancer. In the final talk, Steven Lipkin of Weill Cornell Medical College described research linking the mechanisms of the primary chemotherapy in colorectal cancer, 5-fluorouracil, and a drug being tested for chemoprevention, difluoromethylornithine.
Use the tabs above to find a meeting report and multimedia from this event.
Presentations available from:
Lewis C. Cantley, PhD (Beth Israel Deaconess Medical Center and Harvard Medical School)
Marcia C. Haigis, PhD (Harvard Medical School)
Steven M. Lipkin, MD, PhD (Weill Cornell Medical College)
Joshua D. Rabinowitz, PhD (Princeton University)
Gary Siuzdak, PhD (The Scripps Research Institute, California)
Craig Thompson, MD (Memorial Sloan-Kettering Cancer Center)
Lewis C. Cantley
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Bell EL, Emerling BM, Ricoult SJH, Guarente L. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene 2011;30(26):2986-2996.
Locasale JW, Vander Heiden MG, Cantley LC. Rewiring of glycolysis in cancer cell metabolism. Cell Cycle 2010;9(21):4253.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009;324(5930):1029-1033.
Wang Z, Chatterjee D, Jeon HY, et al. Exon-centric regulation of pyruvate kinase M alternative splicing via mutually exclusive exons. J. Mol. Cell. Biol. 2011.
Marcia C. Haigis
Finley LWS, Haas W, Desquiret-Dumas V, et al. Succinate dehydrogenase is a direct target of sirtuin 3 deacetylase activity. PLoS ONE 2011;6(8):e23295.
Finley LWS, Carracedo A, Lee J, et al. SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization. Cancer Cell 2011;19(3):416-428.
Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 2010;5:253-295.
Lomb DJ, Laurent G, Haigis MC. Sirtuins regulate key aspects of lipid metabolism. Biochim. Biophys. Acta. 2010;1804(8):1652-1657.
Verdin E, Hirschey MD, Finley LWS, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem. Sci. 2010;35(12):669-675.
Steven M. Lipkin
Lipkin SM, Chao EC, Moreno V, et al. Genetic variation in 3-hydroxy-3-methylglutaryl CoA reductase modifies the chemopreventive activity of statins for colorectal cancer. Cancer Prev. Res. (Phila). 2010;3(5):597-603.
Power DG, Gloglowski E, Lipkin SM. Clinical genetics of hereditary colorectal cancer. Hematol. Oncol. Clin. North Am. 2010;24(5):837-859.
Shin Y, Hencey B, Lipkin SM, Shen X. Frequency domain analysis reveals external periodic fluctuations can generate sustained p53 oscillation. PLoS ONE 2011;6(7):e22852.
Sikandar SS, Pate KT, Anderson S, et al. NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer. Cancer Res. 2010;70(4):1469-1478.
Sikandar S, Dizon D, Shen X, et al. The class I HDAC inhibitor MGCD0103 induces cell cycle arrest and apoptosis in colon cancer initiating cells by upregulating Dickkopf-1 and non-canonical Wnt signaling. Oncotarget 2010;1(7):596-605.
Joshua D. Rabinowitz
Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009;462(7274):739-744.
Kamphorst JJ, Fan J, Lu W, White E, Rabinowitz JD. Liquid chromatography-high resolution mass spectrometry analysis of fatty acid metabolism. Anal. Chem. 2011;83(23):9114-9122.
Lu W, Clasquin MF, Melamud E, et al. Metabolomic analysis via reversed-phase ion-pairing liquid chromatography coupled to a stand alone orbitrap mass spectrometer. Anal. Chem. 2010;82(8):3212-3221.
Vander Heiden MG, Locasale JW, Swanson KD, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 2010;329(5998):1492-1499.
Yuan J, Bennett BD, Rabinowitz JD. Kinetic flux profiling for quantitation of cellular metabolic fluxes. Nat. Protoc. 2008;3(8):1328-1340.
Nordström A, Want E, Northen T, Lehtiö J, Siuzdak G. Multiple ionization mass spectrometry strategy used to reveal the complexity of metabolomics. Anal. Chem. 2008;80(2):421-429.
Patti GJ, Yanes O, Siuzdak G. Innovation: Metabolomics: the apogee of the omics trilogy. Nat. Rev. Mol. Cell Biol. 2012;13(4):263-269.
Patti GJ, Tautenhahn R, Siuzdak G. Meta-analysis of untargeted metabolomic data from multiple profiling experiments. Nat. Protoc. 2012;7(3):508-516.
Tautenhahn R, Patti GJ, Kalisiak E, et al. metaXCMS: second-order analysis of untargeted metabolomics data. Anal. Chem. 2011;83(3):696-700.
Yanes O, Tautenhahn R, Patti GJ, Siuzdak G. Expanding coverage of the metabolome for global metabolite profiling. Anal. Chem. 2011;83(6):2152-2161.
Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 2010;18(6):553-567.
Lu C, Ward PS, Kapoor GS, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 2012;483(7390):474-478.
Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 2012;483(7390):479-483.
Wellen KE, Thompson CB. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol. Cell 2010;40(2):323-332.
Wise DR, Ward PS, Shay JES, et al. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc. Natl. Acad. Sci. USA 2011;108(49):19611-19616.
Amaravadi RK, Lippincott-Schwartz J, Yin X, et al. Principles and current strategies for targeting autophagy for cancer treatment. Clin. Cancer Res. 2011;17(4):654-666.
Chen H, White E. Role of autophagy in cancer prevention. Cancer Prev. Res. (Phila). 2011;4(7):973-983.
Mathew R, White E. Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. Curr. Opin. Genet. Dev. 2011;21(1):113-119.
Rabinowitz JD, White E. Autophagy and metabolism. Science 2010;330(6009):1344-1348.
Saleem A, Dvorzhinski D, Santanam U, et al. Effect of dual inhibition of apoptosis and autophagy in prostate cancer. Prostate 2012.
Steven S. Gross, PhD
Steven S. Gross is Professor of Pharmacology, Director of the Mass Spectrometry Core Facility and Director of Advanced Training in Pharmacology at the Weill Cornell Medical College. Gross's primary research interest is in cell–cell communication, with a focus on nitric oxide (NO) and reactive molecules as mediators of cell signaling. In the late 1980s, Gross and colleagues made the initial identification of L-arginine as the precursor of NO in blood vessels. They were also first to establish that NOS inhibition elevates blood pressure in animals, demonstrating that NO plays a physiological role in controlling blood pressure and vascular tone. Since then, research efforts have been directed toward elucidating the enzymes and mechanisms that regulate NO synthesis in cells. Results of these basic studies have provided fundamental insights into the therapeutic control of NO synthesis, resulting in core technologies for the creation of ArgiNOx Inc., a biotech start-up that seeks to develop novel NO-based drugs. Gross's research is supported in part by a MERIT Award from the NHLBI. He is a founder and Board Director of the Nitric Oxide Society and chairs the Steering Committee of the Biochemcial Pharmacology Discussion Group (BPDG) at NYAS. Gross received his PhD in Biomedical Science from the Mount Sinai School of Medicine in New York City.
Jennifer Henry, PhD
The New York Academy of Sciences
Jennifer Henry received her PhD in plant molecular biology from the University of Melbourne, Australia, with Paul Taylor at the University of Melbourne and Phil Larkin at CSIRO Plant Industry in Canberra, specializing in the genetic engineering of transgenic crops. She was then appointed as Associate Editor, then Editor, of Functional Plant Biology at CSIRO Publishing. She moved to New York for her appointment as a Publishing Manager in the Academic Journals division at Nature Publishing Group, where she was responsible for the publication of biomedical journals in nephrology, clinical pharmacology, hypertension, dermatology, and oncology. Henry joined the Academy in 2009 as Director of Life Sciences and organizes 35 – 40 seminars each year. She is responsible for developing scientific content in coordination with the various life sciences Discussion Group steering committees, under the auspices of the Academy's Frontiers of Science program. She also generates alliances with outside organizations interested in the programmatic content.
Lewis C. Cantley, PhD
Lewis Cantley is the William Bosworth Castle Professor of Medicine at Harvard Medical School and Director of the Cancer Center at Beth Israel Deaconess Hospital. Throughout his career, Cantley has been interested in the biochemical mechanisms by which growth factors and hormones control cell growth and cell metabolism and the defects in these control mechanisms that lead to diseases such as diabetes, immune disorders, and cancers. In the course of this work, Cantley discovered a cell growth pathway involving the enzyme Phosphoinositide 3-Kinase (PI3K). This pathway is now known to be the most frequently mutated pathway in human cancers. His discoveries have led to the development of drugs to target this pathway for treating cancers. In recognition of his contributions to the understanding of human diseases, Cantley was elected to the American Academy of Arts and Sciences (1999) and the National Academy of Sciences (2001). He has received numerous awards, including the ASBMB Avanti Award for Lipid Research (1998), the Heinrich Weiland Preis for Lipid Research (2000), the Caledonian Prize from the Royal Society of Edinburgh (2002), the American Association of Cancer Research/Pezcoller Award for Cancer Research (2005), the Rolf Luft Award for Diabetes and Endocrinology Research (2009) and the Pasarow Award for Cancer Research (2011).
Craig Thompson, MD
Craig B. Thompson became President and Chief Executive Officer of Memorial Sloan-Kettering Cancer Center (MSKCC) on November 1, 2010. He came to MSKCC from the University of Pennsylvania, where he had served since 2006 as Director of the Abramson Cancer Center and Associate Vice President for Cancer Services of the University of Pennsylvania Health System. Thompson is a board-certified internist and medical oncologist with extensive research experience in cancer, immunology, and translational medicine. His current research focuses on the role that metabolic changes play in the origin and progression of cancer. Thompson is a member of the Institute of Medicine, the National Academy of Sciences, the American Academy of Arts and Sciences, and the Medical Advisory Board of the Howard Hughes Medical Institute.
Marcia C. Haigis, PhD
Marcia C. Haigis is an Assistant Professor in the Department of Cell Biology at Harvard Medical School and a member of the Paul F. Glenn Laboratories for Medical Research. Haigis received her PhD from the University of Wisconsin in 2002 and completed postdoctoral research at MIT. Her current work contributes to the understanding of how mitochondrial sirtuins regulate tumor cell metabolism. Haigis has received a Brookdale Leadership in Aging Award, the Ellison Medical Foundation New Scholar Award, and an American Cancer Society Research Scholar Award.
Steven M. Lipkin, MD, PhD
Steven Lipkin is an Associate Professor Medicine and Genetic Medicine at Weill Cornell Medical Center. Major interests of his include genetic factors that increase colorectal cancer risk, and chemoprevention for pancreatic and colorectal cancer. Lipkin is a board-certified Medical Geneticist and Internist with a focus on genetic testing for gastrointestinal diseases, including the Lynch Syndrome, Familial Adenomatous Polyposis, Hemochromatosis and Hereditary Pancreatic Cancer, among others. He is an internationally recognized authority on early onset and hereditary GI cancer syndromes. He is the author of MAPP-MMR, a bioinformatic program that is used to interpret whether Lynch syndrome missense variants are deleterious muations or benign polymorphisms. Lipkin practices at Weill Medical College of Cornell University and New York-Presbyterian Hospital. He trained in Internal Medicince at Duke University and Medical Genetics at the National Human Genome Research Institute.
Joshua D. Rabinowitz, PhD
Joshua Rabinowitz grew up in Chapel Hill, North Carolina. In 1994, he earned BA degrees in Mathematics and Chemistry from the University of North Carolina. From there, he moved west to Stanford, where he earned his PhD in Biophysics in 1999, followed by his MD in 2001. As he was completing his MD he co-founded Alexza Pharmaceuticals, now a public company with its first product awaiting FDA approval. After four years leading R&D efforts at Alexza, Rabinowitz joined the faculty of Princeton University, where he is currently Professor of Chemistry and Integrative Genomics. His work applies mass spectrometry to study metabolism and its regulation across a diversity of organisms from E. coli to humans. He is particularly interested in quantitative analysis of metabolic flux.
Gary Siuzdak, PhD
Gary Siuzdak is Director of the Scripps Center for Metabolomics and Professor of Chemistry and Molecular Biology at The Scripps Research Institute in La Jolla, California. He is also Faculty Guest at Lawrence Berkeley National Laboratory, and he served as Vice President of the American Society for Mass Spectrometry. His research includes developing novel mass spectrometry-based approaches in metabolomics, nanostructure-based imaging, microorganism analysis, and enzyme activity assays. He has over 170 peer-reviewed publications and two books, Mass Spectrometry for Biotechnology and The Expanding Role of Mass Spectrometry in Biotechnology, 2006 Edition.
Eileen White, PhD
Eileen White received a BS from Rensselaer Polytechnic Institute and a PhD in Biology from SUNY Stony Brook. She was a Damon Runyon Postdoctoral fellow in the laboratory of Bruce Stillman at Cold Spring Harbor Laboratory. She is currently the Associate Director for Basic Science at the Cancer Institute of New Jersey (CINJ), Professor of Molecular Biology and Biochemistry at Rutgers University, and Adjunct Professor of Surgery at UMDNJ. White has served on the Board of Scientific Counselors of the National Cancer Institute (NCI) and the Board of Directors of the American Association for Cancer Research (AACR). She has revieved a MERIT Award from the NCI, an Investigatorship from the Howard Hughes Medical Institute (HHMI), the Red Smith Award from the Damon Runyon Cancer Research Foundation, an Achievement Award from the International Cell Death Society, and a Career Award from the European Cell Death Organization. White is also an elected Fellow of the American Society of Microbiology (ASM) and the American Association for the Advancement of Science (AAAS). She currently serves on the Scientific Review Boards for the Starr Cancer Consortium and the Cancer Prevention Research Institute of Texas (CPRIT), and is a member of the Board of Scientific Advisors for the AACR. White is a member of Varmus's "Big Questions Project" to guide the future of the NCI. Editorial Boards memberships include Genes & Development, The Journal of Cell Biology, Oncogene, Cancer Prevention Research, Molecular Cancer Research, Autophagy, Cell Death and Disease, and Cancer Discovery.
Steven Fischer received his bachelors in chemistry (1981) and masters in chemistry (1991) at California State University, Hayward. In 1986, he joined Agilent Technologies in Santa Clara (previously part of Hewlett-Packard Company), where he has designed and applied HPLC/MS instrumentation for analytical problems for 20 years. He has over 40 United States issued patents in the field of mass spectrometry. He was the 2007 Bill Hewlett Award recipient for outstanding instrument design innovation. He currently is the Marketing Manager, Metabolomics and Proteomics, responsible for Agilent's world wide metabolomics and proteomics program. In that position, he has focused his attention on developing solutions to metabolomics and proteomics analysis with the goal of using the experimental data synergistically to yield deeper biological insight.
Sarah Webb, PhD
Before hanging up her labcoat, Sarah Webb earned a PhD in bioorganic chemistry from Indiana University in Bloomington. Based in Brooklyn, NY, she writes about science, health, and technology for many publications including Scientific American, Discover, Science Careers, Science News, Nature Biotechnology, and ACS Chemical Biology.