Science Webinar Series · GTP. TSC1 . TSC2 . mTOR. mLST8. Raptor . mTORC1 . Growth-Promoting...
Transcript of Science Webinar Series · GTP. TSC1 . TSC2 . mTOR. mLST8. Raptor . mTORC1 . Growth-Promoting...
to login to Twitter and send tweets
Facebook login
if you need help
shows speaker bios
download slides and more info
LinkedIn login
shows slide window
Change the size of any window by dragging the lower left corner. Use controls in top right corner to close or maximize each window.
What each widget does:
shows the video screen
opens the Ask a Question box
Twitter login (#ScienceWebinar)
search Wikipedia
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 [email protected]
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