OCT 30, 2014 03:00 PM PDT

Probing cancer metabolism using isotope tracers to identify therapeutic targets

Speakers
  • Principal Investigator, Metallo Lab, Assistant Professor, Bioengineering, University of California, San Diego
    Biography
      Christian Metallo joined the University of California, San Diego in 2011 and is currently an assistant professor in the Department of Bioengineering. He received his bachelors in chemical engineering from the University of Pennsylvania in 2000 before joining Merck Research Laboratories to conduct bioprocess engineering research.  He received his Ph.D. from the University of Wisconsin-Madison Department of Chemical and Biological Engineering in 2008 and was an American Cancer Society Postdoctoral Fellow in Chemical Engineering at the Massachusetts Institute of Technology.  Christian was the recipient of the Biomedical Engineering Society Rita Schaffer Young Investigator Award in 2012 and is a 2013 Searle Scholar. Dr. Metallo is also the Principal Investigator at the Metallo laboratory which conducts research in the area of systems biology applied to cancer and stem cell metabolism. They utilize stable isotope tracers, mass spectrometry, and computational tools for metabolic flux analysis (MFA) to study the function of metabolism in disease models. Their work aims to characterize the dynamic interplay between metabolism, signal transduction, and cellular fate choices by understanding how intracellular signals and the microenvironment regulate metabolic fluxes. 

    Abstract:

    Oncogenic mutations in isocitrate dehydrogenase 1 (IDH1) or 2 (IDH2) compromise their normal activity and induce NADPH-dependent (D)2-hydroxyglutarate (2HG) production within the cytosol or mitochondria. Given the critical functions of these enzymes in tricarboxylic acid (TCA) metabolism and cellular redox homeostasis, such mutations are likely to cause metabolic reprogramming in tumors. To identify metabolic abnormalities in cells harboring IDH mutations we applied 13C metabolic flux analysis (MFA) to isogenic cells with heterozygous IDH1 mutations. MFA results indicate that IDH1 mutant cells exhibit increased oxidative TCA metabolism and oxygen consumption under hypoxia relative to parental cells. This metabolic phenotype occurs independently of 2HG accumulation and renders IDH1 mutant cells more sensitive to electron transport chain (ETC) inhibition compared to IDH wild-type and IDH2 mutant cells. These data suggest that targeting mitochondrial metabolism may be synthetically lethal in tumors expressing mutant IDH1 and can be combined with strategies that selectively inhibit its neomorphic activity.
    In addition, we have exploited the NADPH-dependent 2HG production by mutant IDH1 and IDH2 to characterize the function of compartmentalized cofactor cycles that occur in cancer cells. Importantly, pathway segregation in distinct organelles has prevented traditional MFA approaches from accurately measuring fluxes within specific compartments. By applying 2H isotope tracers that specifically label NADPH and inducibly expressing IDH1-R132H or IDH2-R172K in the cytosol or mitochondria, respectively, we can reliably quantify NADPH metabolism in each compartment. Using this approach we have elucidated the directionality of metabolic cycles coordinated between the cytosol and mitochondria that are critical for tumor growth.

    Learning objectives:

    • Why are mitochondria important for cancer cell growth?
    • Why would some cancers be more susceptible to cancer targeting than others?

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