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Hybrid Model For Prostate Tumorigenesis
Maria Audi Byrne, University of South AlabamaMMA Florida Chapter Meeting
5:15 – 5:40 PMNovember 20, 2009
Presentation Outline
1. Biology Context: Cell Microenvironments
2. Motivation: Tissue Recombination Expts
3. Two-Step Model of Tumorigenesis
4. Hybrid Computation Model
I. Biology Context: Cell Microenvironments
Core B: Image Fusion
Gore
Core C:Biomath &
BioinformaticsShyr
Project 3:Bone metastasis
Mundy
Vanderbilt-Ingram Cancer Center
Mou
se M
odels o
f Hum
an
Cance
r Conso
rtium
Van
der b
i lt Int e
gr a
tive
Cance
r B
iol o
gy C
en
t er
Prostate Center
Center for Bone Biology VU In
stitu
te
for I
mag
ing
Scie
nces
Brea
st S
PORE
BioMathem
atics
Small animal
imaging
Proteomics
Core A:Protein
collection & Proteomics
Caprioli
Biostatistics
Project 1: Breast Cancer
Moses
Matrisian
TGFeffectors
Vanderbilt University Tumor Microenvironment Network
VUTMEN
Project 2:Prostate Cancer
Hayward & Bhowmick
Paracrine Signaling
Occurs when a cell or tissue produces a factor which acts upon an adjacent tissue. Paracrine
Interactions
Epithelium
Stroma
TGF as a master regulator of host:tumor interactions
Bierie and Moses, Cytokine Growth Factor Reviews, 2006
Core B: Image Fusion
Gore
Core C:Biomath &
BioinformaticsShyr
Project 3:Bone metastasis
Mundy
Vanderbilt-Ingram Cancer Center
Mou
se M
odels o
f Hum
an
Cance
r Conso
rtium
Van
der b
i lt Int e
gr a
tive
Cance
r B
iol o
gy C
en
t er
Prostate Center
Center for Bone Biology VU In
stitu
te
for I
mag
ing
Scie
nces
Brea
st S
PORE
BioMathem
atics
Small animal
imaging
Proteomics
Core A:Protein
collection & Proteomics
Caprioli
Biostatistics
Project 1: Breast Cancer
Moses
Matrisian
TGFeffectors
Vanderbilt University Tumor Microenvironment Network
VUTMEN
Project 2:Prostate Cancer
Hayward & Bhowmick
Prostate Cancer
From Wikipedia:• Prostate cancer is one of the most common
cancers affecting older men in developed countries and a significant cause of death for elderly men (estimated by some specialists at 3%).
• Many men never know they have prostate cancer. Autopsy studies of men who died of other causes have found prostate cancer in thirty percent of men in their 50s, and in eighty percent of men in their 70s. [Breslow et al, 1977]
II. Tissue RecombinationExperiments
Tissue Recombination Experiments
•Normal stromal cells were mixed with altered stromal cells.
• The altered stromal cells were unable to respond to TGF-beta.
• Effect on epithelial cells was observed for different ratios of normal and altered cells.
Drs. Neil Bhowmick and Hal Moses, VUMC
Tissue Recombination Experiments
•100% normal cells normal epithelia
•100% altered cells PIN
•50/50 mixture PIN AND Invasion
Intermediate levels of altered stroma yield the worst epithelial changes.
Drs. Neil Bhowmick and Hal Moses
(Proliferative)
Mathematical modeling of epithelial-stromal interactions
Modeling GoalHow can we define epithelial and stromal cell rules that
(1) are biologically motivated,(2) model correct proliferative behavior,(3) model correct invasive behavior?
Method: Hypothesize a set of simplified biologically motivated rules and use computer simulations to check if they are sufficient to yield expected cell behaviors.
Warning: If successful, we identify rules that are sufficient to explain experimental observations. Discourse between model predictions and further experiments are needed to further validate/refine the model.
III. Two Step Model of Tumorigenesis
Two-Step Model of Tumorigenesis
Experimental Observation
100% Normal Normal
50/50 Mix PIN & Invasion
100% Altered PIN
Two-Step Model of Tumorigenesis
Experimental Observation
100% Normal Normal
50/50 Mix PIN & Invasion
100% Altered PIN
Model
Step 1: Normal PINMorphogen location:
altered stroma
Step 2: PIN InvasiveMorphogen location:
altered stroma
AlteredStroma
NormalEpithelium
ProliferativeEpithelium
InvasiveEpithelium
HGF
1
NormalStroma
NormalEpithelium
ProliferativeEpithelium
InvasiveEpithelium
SDF1
2
NormalStroma
AlteredStroma
NormalEpithelium
ProliferativeEpithelium
InvasiveEpithelium
HGF SDF
1 2
NormalStroma
AlteredStroma
NormalEpithelium
ProliferativeEpithelium
InvasiveEpithelium
HGF SDF
100% Normal Normal Epithelium
21
NormalStroma
AlteredStroma
NormalEpithelium
ProliferativeEpithelium
InvasiveEpithelium
HGF SDF
100% Altered Stroma Proliferative Epithelium
21
NormalStroma
AlteredStroma
NormalEpithelium
ProliferativeEpithelium
InvasiveEpithelium
HGF SDF
50% Altered Stroma Invasive Epithelium
21
IV. Hybrid Computational Model
Hybrid Model
Discrete, Cell-based Component
•Cells are modeled as discrete, individual entities in 2D space.
•Stromal and epithelial cells: 5 cell types.•Stromal cells are ‘normal’ or ‘altered’.•Epithelial cells are ‘normal’, ‘proliferative’ or ‘invasive’.
•Different stromal types secrete different morphogens.
•Epithelial cells progress sequentially from normal to proliferative to invasive if there are threshold levels of the required morphogen.
Hybrid Model
Continuous, PDE Component
•Morphogen production, diffusion and decay is modeled with the heat equation.
•Production rates k1, k2 (s-1)•Diffusion rates D1, D2 •Decay rates kd1, kd2
12
1111
11 , mDmkyxkt
md
n
iii
s
22
2221
22 , mDmkyxkt
md
a
iii
s
Morphogen Concentrations
Simulation Results
PIN
Invasion
Phase Diagram: Transitions Depend Weakly on Production Levels
‘Most Susceptible’ Epithelial Cells
Future Directions
• Are similar step-models workable for other situations in which TGFB is both tumor suppressive and tumor promoting?
• Developing a dynamic model of normal prostate duct development that includes cell division (proliferation) and cell movement (migration). Morphogens robustly regulate and “tune” the prostate geometry for a ‘good’ but stochastic configuration.
• Updating developmental model for wound healing (healthy response to injury) and tumorigenesis (inappropraite response to injury).
Thank You
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