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Systems-Level Analysis of Cancer Metabolism

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Systems Metabolic Engineering

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.

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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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Authors and Affiliations

  1. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

    Paulo A. Gameiro, Christian M. Metallo & Gregory Stephanopoulos

  2. Department of Life Sciences, University of Coimbra, Coimbra, Portugal

    Paulo A. Gameiro

  3. Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA

    Paulo A. Gameiro

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  1. Paulo A. Gameiro
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  2. Christian M. Metallo
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  3. Gregory Stephanopoulos
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Correspondence to Gregory Stephanopoulos .

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  1. Inst. Bioverfahrenstechnik, TU Braunschweig, Gaußstraße 17, Braunschweig, 38106, Germany

    Christoph Wittmann

  2. Science and Technology-KAIST, Dept. Biosystems a. Bioinformatics, Korea Advanced Institute, Guseong-dong 373-1, Daejeon, 305-701, Korea, Republic of (South Korea)

    Sang Yup Lee

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Gameiro, P.A., Metallo, C.M., Stephanopoulos, G. (2012). Systems-Level Analysis of Cancer Metabolism. In: Wittmann, C., Lee, S. (eds) Systems Metabolic Engineering. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-4534-6_11

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