FinalPresentation_ccb2012_marc_shangying_yan
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Transcript FinalPresentation_ccb2012_marc_shangying_yan
Analysis of inhibition of HER2
signaling to apoptotic
transcription factors
Marc Fink & Yan Liu & Shangying Wang
Student Project Proposal
Computational Cell Biology 2012
Goals
- Modeling the signaling pathway of HER2 inhibitor,
Lapatinib, in Breast Cancer Cells
- Analyze the influence factors of cell apoptosis
- Explanation of cell survival rate after treatment
Outline
Brief review
Boolean network model and results
Modeling with ODEs in VCell and COPASI
Analysis of simulation results
Summary and outlook
Mechanistic (process) diagrams
Death ??????
Survival
Lapatinib
HER2
PI3K
p
PDK1
AKT (PKB)
p
FoxO p
p 14-3-3
FoxO
FoxO
FoxO
FoxO
FoxO
ER
Protein
Translation
Translocation
Transcription
Apoptotic
genes
Survival
genes
Translocation
Apoptosis
01/13
Flow chart and strategies
HER2
AKT
FoxO
Lapatinib
IGF1R
RAF
MEK
ERK
FASL
RSK
Lack of experimental
parameters
=> Boolean network
Better understanding of
dynamics
=> ODEs
Analysis of survival rate
=> Stochastic simulation
BIM
BAD
apoptosis
02/13
Boolean network model
HER2
Lapatinib
IGF1R
FoxO
Apoptosis
AKT
Time steps
BIM
apoptosis
=> Average value of
apoptosis is around 0.5 with
simplification.
03/13
Boolean network model
HER2
Lapatinib
IGF1R
FoxO
Apoptosis
AKT
FASL
Time steps
BIM
apoptosis
=> Average apoptosis is
around 0.6 with additional
information.
03/13
Boolean network model
AKT
FoxO
Lapatinib
IGF1R
RAF
MEK
ERK
Apoptosis
HER2
FASL
RSK
BIM
BAD
apoptosis
Time steps
=> Results depend on the
complexity, adding weights
not possible.
03/13
Modeling with ODEs
=> 22 species and 32 reactions, reasonable rates???!!!
04/13
Model reduction and modification
Due to the importance of FOXO
=> Neglect the downstream and add the self regulation
05/13
Model reduction and modification
HER2
AKT
FoxO
Lapatinib
IGF1R
RAF
MEK
ERK
FASL
RSK
BIM
BAD
apoptosis
05/13
Model reduction and modification
Due to the importance of FOXO
=> Neglect the downstream and add the self regulation
HER2
AKT
Lapatinib
HER2_dimer
HER2_dimer*
PI3K
H_PI3K
FoxO
PIP3
PIP2
AKT
Apoptosis
Φ
FoxO_gene
FoxO_mRNA (x)
AKT*
Φ
FoxO (y)
FoxO* (z)
Model reduction and modification
Due to the importance of FOXO
=> Neglect the downstream and add the self regulation
HER2
AKT
Lapatinib
[Birtwistle et al., 2007]
HER2_dimer
HER2_dimer*
PI3K
H_PI3K
FoxO
PIP3
PIP2
AKT
Apoptosis
Φ
FoxO_gene
FoxO_mRNA (x)
AKT*
Φ
FoxO (y)
FoxO* (z)
Self regulation of FOXO
Φ
FoxO_gene
FoxO_mRNA (x)
Φ
FoxO (y)
=> Bistability of the positive feedback loop
FoxO* (z)
06/13
Modified model
=> 14 species and 16 reactions
07/13
Sensitivity analysis in COPASI
Binding of
Laptinib to
HER2
Dimerization of HER2
FOXO
=> Laptinib is important for cancer cell apoptosis
08/13
Analysis of simulation results
Deterministic simulations with parameter scan (Laptinib)
FOXO concentration
With increasing
initial Laptinib
concentration
0 -> 400 nM
09/13
Analysis of simulation results
Deterministic simulations with parameter scan (Laptinib)
Phosphorylation
=> Laptinib is able to stimulate FOXO, crucial to apoptosis 09/13
Analysis of simulation results
Random initial concentrations and constant Laptinib (200nM)
FOXO concentration
=> Initial concentrations influence the effect of Laptinib. 10/13
Analysis of simulation results
Stochastic simulation using Gillespie algorithm (in VCell & C)
High Laptinib
Low Laptinib
11/13
Summary and outlook
Inhibition of HER2 signaling to apoptotic transcription factors
is studied.
Models with different complexities are analyzed.
Laptinib induced inhibition of HER2 is simulated.
Outlook
Improve the stochastic study
Improve the pathway model with more details by getting
more rates from experiments
Measurement of concentrations within small time scale before
and after treatment will help to understand the whole
signaling process and validate the model.
12/13
Experience with the softwares
COPASI
vs
VCell
Writing reactions
+
+++
Checking parameters
+
+++
Deterministic simulation
+++
+
Stochastic simulation
++
+
Parameter scan
+++
++
Sensitivity analysis
+++
-
-
+++
Visualization
13/13
Happy Birthday
to Nina!