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Webinar Series Science METABOLIC CHANGES IN CANCER:

Beyond the Warburg Effect 19 April, 2012

Sponsored by:

Participating Experts:

Matt Vander Heiden, M.D., Ph.D. Massachusetts Institute of Technology Cambridge, MA

Morris J. Birnbaum, M.D., Ph.D. University of Pennsylvania Philadelphia, PA

Brought to you by the Science/AAAS Custom Publishing Office

Webinar Series Science METABOLIC CHANGES IN CANCER:

Beyond the Warburg Effect 19 April, 2012

Brendan D. Manning, Ph.D. Harvard University, School of Public Health Boston, MA

Morris J. Birnbaum

Institute for Diabetes, Obesity and Metabolism

Perelman School of Medicine University of Pennsylvania

Nutritional abundance in mammals

Extracellular signals: hormones, nutrients, neurotransmitters

Intracellular signaling and metabolic pathways

Nutrient storage Growth

IGF-1 receptor

Akt

Organismal growth

IRS

PI 3-kinase

H. sapiens

Insulin receptor

Akt

Nutrient Storage

IRS

PI 3-kinase

Nutrient abundance

D. melanogaster

Insulin receptor

Akt

Organismal growth

IRS/Chico

PI 3’-kinase

Overexpression of Akt in the fly eye

Wild-type Dakt1

The role for Akt in mammalian growth

Akt1 -/- Akt2 +/-

Akt1 +/+ Akt2 +/+

Akt1 -/- Akt2 +/+

Akt1/PKBα

Akt2/PKBβ

Akt3/PKBγ

The role for Akt in mammalian metabolism

Wildtype

Akt2(-/-)

Akt1(+/-)Akt2(-/-)

0 30 60 90 120

Time (minutes)

Bloo

d gl

ucos

e (m

g/dl

)

Glucose tolerance test 350

300

250

200

150

100

50

0

Akt1(-/-)Akt2(+/-)

Akt1/PKBα

Akt2/PKBβ

Akt3/PKBγ

Growth and metabolism in Akt null liver

Liver weight

Perc

ent b

ody

wei

ght

WT Akt1,2LKO

Glyc

ogen

(mg/

gm li

ver)

60

40

20

0

WT Akt1,2LKO

Liver glycogen

Fasted

Refed

Lipid metabolism in Akt null liver

WT Akt1,2LKO WT Akt1,2LKO

Trig

lyce

ride

(mg/

gm li

ver)

40

30

20

10

0

Palm

itate

(µg/

mg

liver

)

4

3

2

1

0

Liver triglyceride Liver fatty acid synthesis

Glucose

ATP Macromolecule Synthesis

Nutrient storage

IGF1/Insulin

Akt

Growth Differentiation

A phylogenetically conserved pathway to regulate growth and nutrient flux

Glucose

ATP Macromolecule Synthesis

Nutrient storage

IGF1/Insulin

Akt

Growth Differentiation

Glucose

ATP Macromolecule Degradation

Stored nutrients

AMPK

X

Anabolic Catabolic

Anabolic - Akt

Glucose

Catabolic - AMPK

Glucose

Sponsored by:

Participating Experts: Morris J. Birnbaum, M.D., Ph.D. University of Pennsylvania Philadelphia, PA

Brought to you by the Science/AAAS Custom Publishing Office

Webinar Series Science METABOLIC CHANGES IN CANCER:

Beyond the Warburg Effect 19 April, 2012

Brendan D. Manning, Ph.D. Harvard University, School of Public Health Boston, MA

Matt Vander Heiden, M.D., Ph.D. Massachusetts Institute of Technology Cambridge, MA

Metabolic changes in cancer

Matthew Vander Heiden

Koch Institute for Integrative Cancer Research at MIT Dana-Farber Cancer Institute

Tumor cell metabolism

X

Clinical FDG-PET Scanning Exploits Cancer Metabolism

Cancer: Principles & Practice of Oncology 9th Edition

Non-Hodgkins Lymphoma Pre/Post CHOP-R

Courtesy of Dr. A. Van den Abbeelle DFCI

Cell proliferation requires the conversion of nutrients into biomass

NUTRIENTS

ATP

Non-proliferating Cells

Proliferating Cancer Cells

Most of the increased nutrient uptake in cancer is used to support biosynthesis

Cellular nutrient uptake is in excess of ATP demand

0

1

2

3

4

5

6

7

8

0 24 48 72

Cell

Num

ber (

x10^

6 )

Time (hours)

DFCI-1

αMEM/F12

Proliferating Non-proliferating

-500.00

-400.00

-300.00

-200.00

-100.00

0.00

100.00

200.00

300.00

400.00

500.00

Nut

rient

Con

sum

ptio

n /

Prod

uctio

n (m

g/L)

Ctrl +KCN

OX PHOS EXTRACELLULAR METABOLITE FLUX

Glucose

Lactate

Cellular nutrient uptake is in excess of ATP demand

-500.00

-400.00

-300.00

-200.00

-100.00

0.00

100.00

200.00

300.00

400.00

500.00

Nut

rient

Con

sum

ptio

n /

Prod

uctio

n (m

g/L)

+KCN

EXTRACELLULAR METABOLITE FLUX

Glycolysis

OX PHOS

~10%

Acetyl CoA

Glutamine is the major source of carbon for lipid synthesis when oxygen levels are low

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Glucose oxidation

Glutamine reduction

pmol

pal

mita

te/h

r per

106

cel

ls Normoxia

Hypoxia

0%

20%

40%

60%

80%

100%

Normoxia Hypoxia

% c

ontr

ibut

ion

to p

alm

itate

Glucose oxidation Glutamine reduction

Acetyl CoA

Nucleotide Synthesis

Glucose

Glutamine

α-ketoglutarate

P Y

PK-M2

Growth Signal

PK-M2 activity is regulated by cell growth signals and promotes anabolic metabolism

GLUCOSE

PYRUVATE

CO2

LACTATE

PEP PK-M1

Differentiated Cells Oxidative Phosphorylation

Proliferating Cells Aerobic Glycolysis

PYRUVATE

CO2

LACTATE

GLUCOSE

PEP

PK-M2 P-Tyr

Growth Signals

Amino Acids Nucleotides

NADPH ADP

ATP

ADP

ATP ADP

ATP

ANABOLIC METABOLISM

PKM2

3-PG

2-PG

PEP

P-Serine Serine P-HP

NAD NADH

Glycine

Folate Pool / 1 C Metabolism

NADH NAD

Glucose

Lipids

Nucleotides

pTyr Signaling ATP

PYRUVATE

CO2

LACTATE

Glutamate αKG

Glutamine

PHGDH

PKM2 regulates an anabolic program to support cancer cell proliferation

AcCoA

Serine

CO2

ATP PK-M1

Active PK-M2

Will Israelsen Amelia Yu Shawn Davidson Sophia Lunt Zach Johnson Katie Mattaini Brian Fiske Jared Mayers Vinayak Muralidhar Natalie Vokes Gary Bellinger Tahsin Khan NIH NCGC Matt Boxer Jack Jiang Doug Auld Craig Thomas

HMS Dimitrios Anastasiou Jason Locasale Heather Christofk Lewis Cantley Agios Lenny Dang Hua Yang

Acknowledgements

Funding Burroughs Wellcome Fund Damon Runyon Foundation Smith Family Stern Family NCI / NIH Starr Cancer Consortium

MIT Sarah Fendt Greg Stephanopoulos

Talya Dayton Tyler Jacks

Eric Bell

Scott Malstrom

UCSD Christian Metallo

Sponsored by:

Participating Experts: Morris J. Birnbaum, M.D., Ph.D. University of Pennsylvania Philadelphia, PA

Brought to you by the Science/AAAS Custom Publishing Office

Webinar Series Science METABOLIC CHANGES IN CANCER:

Beyond the Warburg Effect 19 April, 2012

Brendan D. Manning, Ph.D. Harvard University, School of Public Health Boston, MA

Matt Vander Heiden, M.D., Ph.D. Massachusetts Institute of Technology Cambridge, MA

Linking Oncogenic Signaling to Tumor Cell Metabolism

Brendan D. Manning

Dept. of Genetics & Complex Diseases Harvard University, School of Public Health

Stress Nutrients

Stress Nutrients

Endocrine Factors (growth factors, mitogens, hormones, cytokines)

Stress Nutrients

Endocrine Factors (growth factors, mitogens, hormones, cytokines)

Growth

Proliferation Death

Differentiation

Stress Nutrients

Growth

Proliferation Death

Differentiation

Metabolic Changes

Endocrine Factors

Signaling Networks

Stress Nutrients

Growth

Proliferation Death

Differentiation

Metabolic Changes

Endocrine Factors

Oncogenic Signaling

mTOR mLST8 Raptor

mTORC1

Amino Acids Glucose

ATP

Growth Factors

Oxygen Cytokines

Insulin

Stress

mTOR complex 1 (mTORC1) senses cellular growth conditions and promotes growth and proliferation

Anabolic Catabolic

Anabolic Cell Growth and Proliferation

PI3K

Rheb

RTK

Akt

PTEN

TSC1- TSC2

Anabolic Cell Growth and Proliferation

GPCR Growth Factors

mTOR LST8 Raptor

mTORC1

Hypoxia

Energy Stress

Wnt Signaling

Inflammation

Amino Acids

AMP

Ras

Raf

MEK

AMPK

ERK

RSK

IKKβ

LKB1 GSK3β

Frz

Wnt

Dvl

NF1

REDD1 HIFα

TNFR

TNFα

Rag

Glucose

Cytokines

Hormones

Rheb

Rheb

GDP

GTP

TSC1 TSC2

mTOR mLST8 Raptor

mTORC1

Growth-Promoting Conditions Poor Growth Conditions

Anabolic Cell Growth and Proliferation

The TSC1-TSC2 complex integrates signals from

cellular growth conditions to regulate mTORC1

Rheb

Rheb

GDP

GTP

TSC1 TSC2

mTOR mLST8 Raptor

mTORC1

Anabolic Cell Growth and Proliferation

EGFR HER2 MET BCR-ABL RAS RAF PI3K AKT Wnt

Oncogenes Tumor Suppressors

PTEN INPP4B NF1 LKB1 ATM

mTORC1 is aberrantly activated in most human cancers

Autophagy Protein Synthesis

Rheb

Rheb

GDP

GTP

TSC1 TSC2

mTOR mLST8 Raptor

mTORC1

Anabolic Cell Growth and Proliferation

EGFR HER2 MET BCR-ABL RAS RAF PI3K AKT Wnt

Oncogenes Tumor Suppressors

PTEN INPP4B NF1 LKB1 ATM

mTORC1 is aberrantly activated in most human cancers

Autophagy Protein Synthesis

Rheb

Rheb

GDP

GTP

TSC1 TSC2

mTOR mLST8 Raptor

mTORC1

X Rapamycin

?

Anabolic Cell Growth and Proliferation

Disruption of the TSC1-TSC2 complex leads to

constitutive activation of mTORC1

EGFR HER2 MET BCR-ABL RAS RAF PI3K AKT Wnt

Oncogenes Tumor Suppressors

PTEN INPP4B NF1 LKB1 ATM

An approach to define the cell intrinsic effects of mTORC1 activation

Tsc1-/- Tsc1-/- +Rap

WT Tsc2-/- Tsc2-/- +Rap mTORC1: OFF ON OFF

Serum-free Growth Conditions

mTORC1-regulated Transcripts

Genomics Metabolomics

mTORC1-regulated Metabolites

mTORC1 stimulates specific metabolic pathways Düvel et al. 2010 Mol Cell

Glucose Glucose 6-P

Fructose 1,6-bis-P

Glyceraldehyde 3-P

ATP

Hk1

Pfkp

Lactate

Fructose 6-P Gpi1

DHAP NAD

NADH

Aldoa

Tpi1 Gapdh

1,3-Bisphosphoglycerate (BPG) ADP

3-Phosphoglycerate

Pgm2 2-Phosphoglycerate

Pyruvate ATP

Pkm2 ADP

Phosphoenolpyruvate Eno1

Glut1

Ldh1 PDH Acetyl-CoA TCA Ox-Phos

Pdk1 mitochondria

Citrate

6-Phosphoglucono-δ-lactone

Pfkl 6-Phosphogluconate

Ribulose 5-P

Ribose 5-P

Xylulose 5-P Rpe

NADP NADPH

Rpia

Pgd

G6pd NADP NADPH

Pgls

Slc25a1

Hk2

Acetyl-CoA

Acly Acc

Malonyl-CoA

Sterols & Isoprenoids

Fatty Acids & Membrane

3-HMG-CoA

Mevalonate

Hmgcs

Hmgcr

Mvk Acsl3

Hsd17b7

Sc5d

Elovl5

Scd1

Elovl1

Hsd17b12 Tkt

Fasn

Acetate Acss2

Pgm1

Ggps1 Fads2

Agpat5

Taldo1

2,3-BPG Bpgm

Gdpd1

Soat1

mTORC1-induced genes: Glycolysis Pentose Phosphate Pathway Lipid/sterol biosynthesis

Düvel et al. 2010 Mol Cell

Pgk1

Glucose Glucose 6-P

Fructose 1,6-bis-P

Glyceraldehyde 3-P

ATP

Hk1

Pfkp

Lactate

Fructose 6-P Gpi1

DHAP NAD

NADH

Aldoa

Tpi1 Gapdh

1,3-Bisphosphoglycerate (BPG) ADP

3-Phosphoglycerate

Pgm2 2-Phosphoglycerate

Pyruvate ATP

Pkm2 ADP

Phosphoenolpyruvate Eno1

Glut1

Ldh1 PDH Acetyl-CoA TCA Ox-Phos

Pdk1 mitochondria

Citrate

6-Phosphoglucono-δ-lactone

Pfkl 6-Phosphogluconate

Ribulose 5-P

Ribose 5-P

Xylulose 5-P Rpe

NADP NADPH

Rpia

Pgd

G6pd NADP NADPH

Pgls

Slc25a1

Hk2

Acetyl-CoA

Acly Acc

Malonyl-CoA

Sterols & Isoprenoids

Fatty Acids & Membrane

3-HMG-CoA

Mevalonate

Hmgcs

Hmgcr

Mvk Acsl3

Hsd17b7

Sc5d

Elovl5

Scd1

Elovl1

Hsd17b12 Tkt

Fasn

Acetate Acss2

Pgm1

Ggps1 Fads2

Agpat5

Taldo1

2,3-BPG Bpgm

Gdpd1

Soat1

mTORC1-induced genes: Glycolysis Pentose Phosphate Pathway Lipid/sterol biosynthesis

Düvel et al. 2010 Mol Cell

Pgk1

SREBP1/2 Targets

SREBP1

HIF

1α T

arge

ts

Autophagy Protein Synthesis

Glucose Uptake

Glycolysis Pentose Phosphate Pathway

De novo Lipid

Synthesis

HIF1 SREBP

Rheb

Rheb

GDP

GTP

TSC1 TSC2

mTOR mLST8 Raptor

mTORC1

Düvel et al. 2010 Mol Cell

Autophagy Protein Synthesis

Glucose Uptake

Glycolysis Pentose Phosphate Pathway

De novo Lipid

Synthesis

Metabolic Hallmarks of Cancer

* * * *

*

Rheb

Rheb

GDP

GTP

TSC1 TSC2

mTOR mLST8 Raptor

mTORC1

HIF1 SREBP

Düvel et al. 2010 Mol Cell

Autophagy Protein Synthesis

Glucose Uptake

Glycolysis Pentose Phosphate Pathway

De novo Lipid

Synthesis

Metabolic Hallmarks of Cancer

* * * *

*

Rheb

Rheb

GDP

GTP

TSC1 TSC2

mTOR mLST8 Raptor

mTORC1

EGFR HER2 MET BCR-ABL RAS RAF PI3K AKT Wnt

Oncogenes Tumor Suppressors

PTEN INPP4B NF1 LKB1 ATM

HIF1 SREBP

Glucose

Amino Acids

Glucose-6P

Pyruvate

Ribose PPP

Gly

coly

sis

Lactate

Mitochondria

Nucleotides

ATP Precursors

NADPH

Citrate Ac-CoA

Fatty Acids Sterols Isoprenoids

Membranes

Lipi

d &

Ste

rol

Syn

thes

is Protein

Prot

ein

Synt

hesi

s

Aut

opha

gy

mTORC1

mTORC1 promotes biosynthetic processes to drive cell growth

Environmental Factors (e.g., Dietary, Infectious)

Chronic mTORC1 Signaling

Carcinogenesis

Perturbation of Tissue

Tissues Oncogenic Events

(e.g., PI3K, Ras)

Chronic mTORC1 Signaling

Tumor Growth and Progression

Tumors

Anabolic Metabolism

Potential dual role of mTORC1 in cancer initiation and progression

Menon et al. 2012 Science Signaling

Past Members Alex Lipovsky Jingxiang Huang Hui Zhang Katrin Düvel Jessica Yecies Christian Dibble

Manning Lab Sue Menon Yinan Zhang Jessica Howell Justin Nicholatos Stéphane Ricoult Issam Ben Sahra

Leon Murphy Novartis

Clary Clish Broad Institute

John Asara BIDMC, HMS

Rod Bronson HMS

David Kwiatkowski BWH, HMS

Thank You

Sponsored by:

Participating Experts: Morris J. Birnbaum, M.D., Ph.D. University of Pennsylvania Philadelphia, PA

Brought to you by the Science/AAAS Custom Publishing Office

Webinar Series Science METABOLIC CHANGES IN CANCER:

Beyond the Warburg Effect 19 April, 2012

Brendan D. Manning, Ph.D. Harvard University, School of Public Health Boston, MA

To submit your questions, type them into the text box

and click . Matt Vander Heiden, M.D., Ph.D. Massachusetts Institute of Technology Cambridge, MA

Look out for more webinars in the series at: webinar.sciencemag.org

For related information on this webinar topic, go to:

www.cellsignal.com

To provide feedback on this webinar, please e-mail your comments to webinar@aaas.org

Sponsored by:

Brought to you by the Science/AAAS Custom Publishing Office

Webinar Series Science METABOLIC CHANGES IN CANCER:

Beyond the Warburg Effect 19 April, 2012