Cancer Metabolomics: Elucidating the Biochemical Programs that Support Cancer Initiation and Progression

Agenda

* Presentation times are subject to change.

Abstracts

Putting the Brakes on Cancer Cell Metabolism
Craig B. Thompson, MD, Memorial Sloan-Kettering Cancer Center

Proliferating cancer cells exhibit a robust but seemingly wasteful metabolism. Two nutrients, glucose and glutamine, are consumed by tumor cells at rates in vast excess of their utilization by non-transformed cells. The uptake of each of these nutrients is under the control of distinct oncogenes. The PI3K/Akt/TOR signaling pathway plays the primary role in directing cellular glucose uptake and metabolism. Deregulation of this pathway in cancer can be imaged in vivo by FDG-PET scans. In contrast, the myc family of oncogenes direct glutamine uptake and mitochondrial catabolism in transformed cells. Glutamine and glucose metabolism facilitate distinct mitochondrially-dependent synthetic reactions required for growth. Recent evidence suggests tumor suppressors are counter-regulators of mitochondrial biosynthesis. In the case of hypoxia, conversion to anaerobic glycolysis is induced by activation of HIF-1α. In the case of glucose limitation, conversion to fatty acid oxidation is mediated by activation of p53. In addition, a role for intracellular metabolites in oncogenic signaling has also been recently suggested through studies of succinate dehydrogenase and fumarase mutations in cancer. The discovery of cancer-associated mutations in isocitrate dehydrogenase that produce a novel metabolite, 2-hydroxyglutarate, provides the most compelling example of this principle to date. With these new discoveries in mind, the roles of oncogenes and tumor suppressors in the regulation of metabolic pathways will be discussed. Therapeutic strategies to selectively impair tumor metabolism will be considered.

Untargeted Metabolomics Reveals Shared Metabolic Changes for the Induction of Oncogenesis
Gary Siuzdak, PhD, The Scripps Research Institute, California

Untargeted metabolomics, the quantitative global analysis of endogenous metabolites from cells, tissues, fluids and whole organisms, is becoming an integral part of functional genomics efforts as well as a tool for understanding fundamental biochemistry. Our experimental aim is to obtain a comprehensive quantitative view of the metabolome in order to expand our understanding of what pathways are altered in specific diseases—a central question in the emerging field of therapeutic metabolomics. In order to accomplish this goal we have developed a novel mass spectrometry-based platform for metabolomics including XCMS data analysis combined with Metlin (a comprehensive MS/MS metabolite database) as well as nanostructure-initiator mass spectrometry (NIMS) imaging. These technologies will be presented in the context of their application to discovering new therapeutic targets/pathways in oncology.

SIRT3 Loss, Mitochondrial Oxidative Stress and HIF1-α Stabilization: A Triggering Cascade for Tumorigenesis and Warburg Metabolism
Marcia C. Haigis, PhD, Harvard Medical School

One hallmark feature of tumor cells is a shift from oxidative to glycolytic metabolism, and this reliance on aerobic glycolysis to support cell growth is known as the Warburg effect. Mitochondrial sirtuins are NAD-dependent enzymes that bind and regulate numerous metabolic pathways within the mitochondria. For example, SIRT3 functions as an NAD-dependent deacetylase that binds and activates numerous oxidative pathways. We have discovered that SIRT3 has an additional effect on cellular metabolism by repressing cellular glycolysis through the regulation of HIF1 a transcription factor that increases gene expression of glycolytic targets. SIRT3 null cells exhibit metabolic and genetic features of the Warburg effect and enhanced tumorigenecity in vivo. Likewise, SIRT3 overexpression reduces glycolysis in tumor cells. In sum, a better understanding of sirtuin-mediated regulation may identify novel ways to therapeutically target tumor metabolism.

How Do Cancer Cells Acquire Fatty Acids?
Joshua D. Rabinowitz, PhD, Princeton University

Cell proliferation requires replication of the plasma membrane and internal lipid structures. How do cells acquire the required fatty acids? What is the impact of oncogenes on this process? Fatty acids are synthesized using three fundamental components: (i) acetyl-CoA, (ii) ATP, and (iii) NADPH. We have used liquid chromatography-mass spectrometry (LC-MS) and isotope tracers to investigate how each of these components is produced in cultured cells expressing activated Akt or Ras. In addition, to examine fatty acid biosynthetic reactions directly, we have developed a LC-MS method for long-chain and very-long-chain fatty acid analysis. The method enables quantitation of molecular ion peaks for all labeled forms of each fatty acid, and thereby isotope tracer-based analysis of fatty acid metabolism. Its application reveals substantial differences in fatty acid acquisition routes between Akt and Ras driven cells, with Akt favoring de novo lipogenesis and Ras favoring scavenging of serum lipids. The potential for these differences to impact the sensitivity of tumors to lipid metabolic enzyme inhibitors will be discussed.

Role of Autophagy in Cancer Metabolism
Eileen P. White, PhD, The Cancer Institute of New Jersey, Rutgers University

The cellular self-cannibalization process of autophagy is activated by stress and starvation to capture proteins and organelles and deliver them to the lysosomal compartment for degradation. The resulting breakdown products, such as amino acids, sugars, nucleosides, and lipids, are then released into the cytoplasm where they can be recycled to sustain metabolism or used for generation of new biomass. Normal cells use autophagy to survive interruptions in growth factor and nutrient availability and to eliminate damaged proteins and organelles, the accumulation of which is toxic. Autophagy has a dual role in cancer. Loss of autophagy normal tissue results in damage, inflammation and genome instability resulting from failure of protein and organelle quality control that can promote cancer initiation. In this context autophagy is a tumor suppression mechanism, particularly in the liver. In tumors, autophagy is activated by stress in the microenvironment and supports cancer cell survival. Autophagy is also upregulated in established cancers and supports metabolism, stress survival, therapy resistance and tumorigenesis. In these contexts autophagy is tumor promoting. The role of autophagy in the settings of cancer initiation, progression and therapy, and its functional role in protein and organelle quality control and in metabolism will be discussed. Insights from autophagy modulation in genetically engineered mouse models for cancer, and in the context of cancer therapy, will be addressed.

Cancer Cell Metabolism
Lewis C. Cantley, PhD, Beth Israel Deaconess Medical Center and Harvard Medical School

Cancer cells have a greater demand for NADPH than most non-cancerous cells because of an increased demand of this reducing potential to combat ROS and to synthesize fatty acids and nucleic acids. A failure to meet this demand can result in cell stasis or cell death. This greater demand for NADPH can be achieved by altering pathways for glucose and glutamine metabolism to increase NADPH production, at the expense of decreased ATP synthesis. The particular way that a cancer cell solves this metabolic problem is dictated by the mutational and epigenic changes that occur during tumor development. For example, mutations in the PI3K pathway typically drive tumors into higher rates of glucose consumption and lower rates of oxygen consumption (known as the Warburg Effect). An understanding of the links between oncogenic mutations and their consequent effects on metabolic flux should suggest novel approaches for therapies that combine inhibitors of signal transduction pathways with inhibitors of nodes in metabolic pathways.

Metabolite Profiling Reveals Novel Insights into Mechanism of Action of DFMO, an Ornithine Decarboxylase Inhibitor Effective in Colon Cancer Chemoprevention
Steven M. Lipkin, MD, PhD, Weill Cornell Medical College

Colorectal cancer (CRC) is the 2nd leading cause of cancer death. CRCs develop through a multi-step process that takes several years. The long duration of this process makes chemoprevention an attractive approach to reduce CRC mortality. The most effective CRC chemoprevention regimen to date includes the ornithine decarboxylase inhibitor α-difluoromethylornithine (DFMO), which reduces polyamine levels. However, in DFMO treated patients, mucosal polyamine levels do not correlate with CRC chemopreventative efficacy and the metabolic consequences of DFMO therapy are incompletely characterized. Here, we perform the first global, unbiased metabolomic profiling study of DFMO treated intestinal mucosa. Our study reveals that chronic DFMO therapy unexpectedly causes depletion of S-adenosylmethionine (SAM), which reduces one-carbon metabolism and thymidine synthesis both in vitro and in vivo. Reduced thymidine levels impair cellular proliferation. Thymidine repletion rescues this defect. Since 5-fluorouracil reduced cellular thymidine is the cornerstone of anti-CRC chemotherapy, this study reveals the first shared mechanism for CRC chemoprevention and therapy and suggests commonalities between pre-malignant and malignant colonocytes. Our study also raises an unanticipated concern that dietary folate and SAM could reduce DFMO efficacy and confound an ongoing FDA registrational CRC chemoprevention trial of DFMO and sulindac.

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