Cancer Metabolism Reinvention of Hallmark of Cancer

Miroslava Cuperlovic-Culf, Ph.D.

Senior Research Officer, National Research Council of Canada

Adjunct Professor, Mount Allison University

from Moncton, NB, Canada

22. May, 2012

TissueCancer analysisDiagnosticPrognostic Organism

Treatment assessmentDiagnosticRisk assesment

Cell

Cancer analysisDrug discoveryDiagnostic

ALTERED METABOLISM:CAUSE or EFFECT OF CANCER

Genetic changes of oncogenes andOncosuppressors

Cancer metabolic phenotype

Tumour microenvironment(pH, hypoxia, nutrient deprivation, autophagy)

Bioenergetics

Biosynthesis

Oxidative state

Glucose

Glucose

PEP

Pyruvate

G6P

Lactate + H+

Lactate +H+

R5P

AcetylCoA

Citrate

aKG

Amino Acids Import

Citrate

Acetyl CoA

Fatty acids

Glutamate

H2CO3

H++ CO2

GLUT1

ATP

ADPGLY

COLY

SIS

Cholesterol

PPP

CANCER METABOLIC PHENOTYPE

FATT

Y AC

IDSY

NTH

ESIS

NUCLEOTIDESSYNTHESIS

AMINO ACIDSYNTHESIS

Fatty acids

MYCHIF1

AKTp53

STAT3

EGFR

SNPAlternative splicingTranscription factorsEpigenetics

miRNA;Translation kinetics

AbilityDesire

Strategy

Action

Protein activation/inhibitionProtein interactions

Cuperlovic-Culf, et al. Exp Opin Mol Diagn 2008; Cuperlovic-Culf, et al. DDT 2010; Cuperlovic-Culf, NMR Metabolomics in Cancer Research. Oxford Biosciences, 2013

LN229

BS149

LN319

LN18

A172

U343

LN405

U373

HS683

Cuperlovic-Culf, et al. Jour Biol Chem 2012

Glioblastoma multiforme the most common and most aggressive malignant primary brain tumor in humans: median survival 3months – 2 years (with treatment)

1 2 3 4

SAM method: Tusher, et al. PNAS, 2001

Microarray data from: Grzmil, et al. Cancer Res, 2001, GSE15824 Wiedemeyer, et al. Cancer Cell 2008, GSE9200

overexpression in group Increased metabolites

Group 1:overexpression (red) Increased metabolites

CONCLUSIONS• Metabolic profiling (qualitative and

quantitative) leads to information about tumour subtypes;

• Metabolic biomarkers for tumour subtypes can be related to gene expression characteristics;

FUTURE

CONCLUSIONS FUTURE• Testing of clinical samples for

biomarkers of subtypes discovery and validation;

• Development and testing of drug options for glioblastoma subtypes

THANK YOU/ MERCI

Mohamed TouaibiaPier Jr. Morin

David FergusonMarc Surette

Anissa Belkaid

Rodney OuelletteAdrian CulfNatalie Lefort

Nabil BelacelDan TulpanJason Hines

METABOLITE CANCER NORMALL-Valine

L-LeucineL-Isoleucine

73.01(1.36) 110.53(9.12)

L-Lysine 10.31(1.36) 20.55(2.21)L-Alanine 11.62(1.54) 16.35(1.1)

L-Aspartic acid 0.77(0.08) 2.65(0.71)Phenylalanine 6.06(0.96) 11.12(1.88)

Tyrosine 0.25(0.12) 0.50(0.14)Glutamine 5.53(0.83) 3.44(0.81)

Total Choline 13.93(5.32) 6.58(1.84)UDP-glucose 6.59(0.75) 1.63(1.63)

Lactic acid 58.29(13.84) 56.47(18.19)

METABOLITE IDC (ER+) AC (ER-)L-Valine

L-LeucineL-Isoleucine

78.05(1.76) 67.98(6.10)

Glycerol-3-phosphate 50.31(4.56) 38.27(2.12)

L-Alanine 12.06(0.59) 11.17(2.05)

L-Aspartic acid 0.79(0.07) 0.74(0.09)Phenylalanine 6.82(0.62) 5.23(0.51)

Tyrosine 0.26(0.08) 0.24(0.16)Choline 15.02(5.01) 12.84(5.66)

Lactic acid 49.2(3.19) 67.39(14.51)

Cuperlovic-Culf, et al. Chem Sci (2011)

BREAST CANCER