Case Studies in Cancer Modelling: Connecting with the Clinic Mark Chaplain School of Mathematics and Statistics Mark Chaplain Multiscale cancer modelling INI 9th December 2015 1 / 54
Case Studies in Cancer Modelling:Connecting with the Clinic
Mark ChaplainSchool of Mathematics and Statistics
Mark Chaplain Multiscale cancer modelling INI 9th December 2015 1 / 54
Talk Overview
Biology of cancer
Intracellular modelling
Cell-scale modelling
Tissue-scale modelling
Applications and Impact
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Cancer: A Nonlinear Dynamical System
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The Hallmarks of Cancer
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The Hallmarks of Cancer
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Cancer: A Multiscale System
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Cancer: A Multiscale System
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Cancer: A Multiscale System
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Intracellular modelling: Gene regulatory networks
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Gene regulatory networks: Transcription Factors andOscillations
Spatio-temporal oscillations in the NF-κB system
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Gene regulatory networks: Negative feedback loops
A generic negative feedback loop: species x produces y which then inhibitsx, in turn reducing levels of y. . .
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The Hes1 Transcription Factor
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Hes1 Spatial Stochastic Model
µp
!m
Pf Po
k1
k2
!m/"
mRNA
!p
#
#protein
µm
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Hes1 Spatial Stochastic Model
Pf + proteink1−−k2
Po, (promoter, xm, nucleus)
Pfαm−−−→ mRNA, (promoter, xm, nucleus)
Poαm/γ−−−−−→ mRNA, (promoter, xm, nucleus)
mRNAαp−−→ mRNA + protein, (cytoplasm,Ωc)
mRNAµm−−−→ φ, (entire cell,Ω)
proteinµp−−→ φ, (entire cell,Ω)
proteiniD/h2
−−−−→ proteini+1, (entire cell,Ω)
mRNAiD/h2
−−−−→ mRNAi+1, (entire cell,Ω)
proteiniD/h2
−−−−→ proteini−1, (entire cell,Ω)
mRNAiD/h2
−−−−→ mRNAi−1, (entire cell,Ω)
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Hes1: Experimental Data/Simulation Results
Experimental data from Kobayashi et al.1 showing Hes1 protein levels in murineembryonic stem cells.
1Kobayashi et al. (2009) The cyclic gene Hes1 contributes to diverse differentiationresponses of embryonic stem cells Genes Dev. 23, 1870 - 1875
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Hes1: Experimental Data/Simulation Results
0 200 400 600 800 10000
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copy
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mRNAprotein
0 200 400 600 800 10000
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0 200 400 600 800 10000
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Corresponding simulation results from the spatial stochastic model1.
1Sturrock, Hellander, Matzavinos, Chaplain (2013) Spatial stochastic modelling ofthe Hes1 gene regulatory network: intrinsic noise can explain heterogeneity in embryonicstem cell differentiation. J. R. Soc. Interface 10, 20120988
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Period Estimation
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Intracellular modelling: p53-Mdm2 System
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Intracellular modelling: p53-Mdm2 System
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Intracellular modelling: p53-Mdm2 System
Experimental data from Lahav et al.2 showing p53 and Mdm2 protein levels inindividual cells.
2Lahav et al. (2004) Dynamics of the p53-Mdm2 feedback loop in individual cells.Nature Genetics 36, 147 - 150
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Intracellular modelling: p53-Mdm2 System
Corresponding simulation results from a spatial stochastic p53 model.Mark Chaplain Multiscale cancer modelling INI 9th December 2015 19 / 54
Diffusion Causes Oscillations: Rigorous Proof
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A Force-based, Individual-based Model of Tumour Growth
cells modelled as elastic spheres
maximum radius of the cells: R= 5 µm
cells divide into two spheres of radius R
213
cell cycle length are uniformly distributed between 17h and 27h
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A Force-based, Individual-based Model of Tumour Growth
Cell-Cell Interaction
cell-cell repulsion calculated by the Hertz model
cell-cell adhesion calibrated with separation force measurements
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A Force-based, Individual-based Model of Tumour Growth
The potential Vij between two cells of radius Ri and Rj is given by
Vij = (Ri +Rj − dij)5/21
5Eij
√RiRj
Ri +Rj︸ ︷︷ ︸repulsive forces
+ εs︸︷︷︸adhesive forces
.
Eij is defined by
Eij =3
4
(1− σ2iEi
+1− σ2jEj
).
Ei, Ej are the elastic moduli of the cells i, j, σi, σj the Poisson ratios ofthe spheres.
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Intercellular Adhesion: E-cadherin and β-catenin
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Intercellular Adhesion: E-cadherin and β-catenin
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Intercellular Adhesion: E-cadherin and β-catenin
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A Force-based, Individual-based Model of Tumour Growth
The interaction force results from deriving the potential function
F ij = −(∂Vij/∂dij)(d(dij)/dx, d(dij)/dy, d(dij)/dz)
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Individual-based, Force-based Model
Cell movement:
Γfisvi︸ ︷︷ ︸
s-friction
+∑j nn i
Γfij
(vi − vj
)︸ ︷︷ ︸cell-cell friction
=∑i nn j
F ij︸ ︷︷ ︸forces
+ fi(t)︸︷︷︸
noise
+ χ∇Q(t)︸ ︷︷ ︸chemotaxis
+ ρ∇H(t)︸ ︷︷ ︸hapotaxis
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Cell-Matrix Interactions
Elements of the model:
cell modelled as flat hemispherical object
I base radius : 15µmI height : 2.6µm
extracellular matrix fibres modelled as rigid cylinders
I length ∼N(75µm, 5µm)I width 200nmI uniformly distributed in 2D space
Cell-Fibre Interaction:
cell polarisation and migration
contact inhibition of locomotion
matrix remodelling
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Cell-Matrix InteractionsMatrix Remodelling - fibre realignment due to adhesion and forcegeneration
a polarised cell pulls fibres towards itself whereby:
fibre is lever that is rotated about the moment of force
end of fibre that is furthest away from cell acts as fulcrum
realignment of fibre dependent on integrin expression and matrixstiffness
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Summary
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Single Cell Simulation
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Multicell Simulation
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Further Single Cell Simulations
Investigation of changes in:
fibre length
fibre density
matrix stiffness
matrix architecture
and the effect on:
cell speed
persistence time
Results:
matrix stiffness has a large influence on cell speed and persistence→ matrix reorientation seems to be a very important process in cellmigration
decrease in matrix isotropy leads to increase in persistence
nonlinear relationships between persistence times and fibre length anddensity
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Further Single Cell Simulations
Investigation of changes in:
fibre length
fibre density
matrix stiffness
matrix architecture
and the effect on:
cell speed
persistence time
Results:
matrix stiffness has a large influence on cell speed and persistence→ matrix reorientation seems to be a very important process in cellmigration
decrease in matrix isotropy leads to increase in persistence
nonlinear relationships between persistence times and fibre length anddensity
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Metastasis
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Chemotherapy and Radiotherapy Treatment Modelling
hybrid cellular automaton - PDE approach
individual cancer cells
cell-cycle
blood vessels
oxygen, chemotherapy drug
radiation
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Chemotherapy and Radiotherapy Treatment Modelling
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Chemotherapy and Radiotherapy Treatment Modelling
Cell-cycle - ODEs in each cancer cell
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Chemotherapy and Radiotherapy Treatment Modelling
Blood vessel distribution - 2D cross-section of tissue
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Chemotherapy and Radiotherapy Treatment Modelling
Oxygen and chemotherapy drug:
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Chemotherapy and Radiotherapy Treatment Modelling
Radiation:
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Chemotherapy and Radiotherapy Treatment Modelling
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Chemotherapy and Radiotherapy Treatment Modelling
Radiation:
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Chemotherapy and Radiotherapy Treatment Modelling
Radiation:
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Chemotherapy and Radiotherapy Treatment ModellingRadiation:
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Cancer Invasion Modelling
Thursday 10th December:15:30 - 16:15 Pia Domschke (Technische Universitat Darmstadt)Mathematical Modelling of cancer invasion: The role of cell adhesionvariability
Friday 11th December11:30 - 12:30 Alf Gerisch (Technische Universitat Darmstadt)Nonlocal models for interaction drive cell movement
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Cancer Invasion Modelling
Thursday 10th December:15:30 - 16:15 Pia Domschke (Technische Universitat Darmstadt)Mathematical Modelling of cancer invasion: The role of cell adhesionvariability
Friday 11th December11:30 - 12:30 Alf Gerisch (Technische Universitat Darmstadt)Nonlocal models for interaction drive cell movement
Mark Chaplain Multiscale cancer modelling INI 9th December 2015 46 / 54
Cancer Invasion Modelling
Thursday 10th December:15:30 - 16:15 Pia Domschke (Technische Universitat Darmstadt)Mathematical Modelling of cancer invasion: The role of cell adhesionvariability
Friday 11th December11:30 - 12:30 Alf Gerisch (Technische Universitat Darmstadt)Nonlocal models for interaction drive cell movement
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Applications and Impact
“The REF”
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Applications and Impact
“The REF”
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Applications and Impact
“The REF”(Unfortunately NOT) “The Last Judgement”
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Applications and Impact
“The REF”(Unfortunately NOT) “The Last Judgement”
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Applications and Impacthttp://www.ref.ac.uk
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Applications and Impact
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Applications and Impact
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Applications and Impact
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Summary
Mathematical models of cancer growth/treatment at multiple scales
Quantitative, predictive
Applications to clinical practice, patient-specific therapy
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Collaborators
Marc Sturrock (ICL)
Ignacio Ramis-Conde (UCLM, Spain), Daniela Schluter (Lancaster)
Gibin Powathil (Swansea)
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