Systems-Level Analysis of Cancer Metabolism

  • Paulo A. Gameiro
  • Christian M. Metallo
  • Gregory Stephanopoulos
Chapter

Abstract

The complexity of cancer requires systems-level approaches to examine uncontrolled proliferation, with many analytical tools now providing massive information on distinct cellular processes. In contrast to the genetic anchors founded in cancer biology that underpin tumor suppressors and oncogenes as units of malignant function, we now see a shift of attention towards metabolism. This trend calls for the increased use of stable isotopic tracers to dissect effects in metabolic fluxes that arise from gene deregulation. When combined with analytical techniques such as mass spectrometry or nuclear magnetic resonance (NMR) and computational tools to interpret such datasets, isotopic tracers can allow for the determination of various metabolic events involved in tumorigenesis at a fine resolution. As such, the interplay between fluxes and signaling warrants a thorough investigation that will lead to targeted therapies rooted on metabolic targets. This chapter describes stable isotopic methods to determine fluxes and identify switches, illustrating how metabolic activity can be quantitatively interpreted to address fundamental questions in cancer.

Keywords

Systems-level analysis Cancer metabolism Cell proliferation Tumor repressor Oncogenes Malignent function Isotopic tracers Nuclear magnetic resonance (NMR) Metabolic flux analysis Anabolic switch Metabolic targets Lipid synthesis Nucleic acid synthesis Protein synthesis Cell culture Tumorgenesis Metabolic markers Metabolomics Mass spectrometry Isotopic enrichment Experimental design Turnover rates Metabolic steady-state Pulse-chase strategy Isotopomer distribution Elemental tracers Non-targeted tracer fate detection (NTFD) Warburg effect Metabolic switch Splice isoform Pyruvate kinase Glutamine Metabolic reprogramming Catabolic arrest 

Abbreviations

2HG

R(2)-2-hydroxyglutarate

AA

Aminoacid

ACL

ATP citrate lyase

AMP

Adenosine 5′-monophosphate

AMPK

AMP-activated protein kinase

ATP

Adenosine 5′-triphosphate

dN

Deoxyribonucleoside

DNNS

De novo nucleoside synthesis

dR

deoxyribose (dR)

EI

Electron impact

EMU

Elementary metabolic unit

ETC

Electron transport chain

FH

Fumarate hydratase

FSR

Fractional synthesis rate

GAP

Glyceraldehyde 3-phosphate

GC

Gas Chromatography

HK-II

Hexokinase II

IDH

Isocitrate dehydrogenase

ISA

Isopotomer spectral analysis

LC

Liquid Chromatography

LDH-A

Lactate dehydrogenase A

MFA

Metabolic flux analysis

MID

Mass isotopomer distribution

m/z

Mass-to-charge ratio

NEAA

Non-essential amino acid

NMFA

Nonstationary metabolic flux analysis

NTFDA

Non-targeted tracer fate detection

OXPHOS

Oxidative phosphorylation

PC

Pyruvate carboxylase

PDH

Pyruvate dehydrogenase

PEP

Phosphoenolpyruvate

PGAM1

Phosphoglycerate mutase

PK

Pyruvate kinase

PPP

Pentose phosphate pathway

TBDMS

Tert-butyldimethylsilyl

TCA

Tricarboxylic acid

TGF-β

Transforming growth factor β

TKT

Transketolase

TMS

Trimethylsilyl

VDAC

Voltage-dependent anionic channel

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Copyright information

© Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Paulo A. Gameiro
    • 1
    • 2
    • 3
  • Christian M. Metallo
    • 1
  • Gregory Stephanopoulos
    • 1
  1. 1.Department of Chemical EngineeringMassachusetts Institute of TechnologyCambridgeUSA
  2. 2.Department of Life SciencesUniversity of CoimbraCoimbraPortugal
  3. 3.Department of MedicineMassachusetts General HospitalBostonUSA

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