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