1. Hybrid Model For Prostate Tumorigenesis Maria Audi Byrne, University of South Alabama MMA Florida Chapter Meeting 5:15 – 5:40 PM November 20, 2009

2. Presentation Outline 1.Biology Context: Cell Microenvironments 2.Motivation: Tissue Recombination Expts 3.Two-Step Model of Tumorigenesis 4.Hybrid Computation Model

3. I. Biology Context: Cell Microenvironments

4. Core B: Image Fusion Gore Core C: Biomath & Bioinformatics Shyr Project 3: Bone metastasis Mundy Vanderbilt-Ingram Cancer Center Mouse Models of Human Cancer Consortium Vanderbilt Integrative Cancer Biology Center Prostate Center Center for Bone Biology VU Institute for Imaging Sciences Breast SPORE BioMathematics Small animal imaging Proteomics Core A: Protein collection & Proteomics Caprioli Biostatistics Project 1: Breast Cancer Moses Matrisian TGF  effectors Vanderbilt University Tumor Microenvironment Network VUTMEN Project 2: Prostate Cancer Hayward & Bhowmick

5. Paracrine Signaling Occurs when a cell or tissue produces a factor which acts upon an adjacent tissue.

6. TGF  as a master regulator of host:tumor interactions Bierie and Moses, Cytokine Growth Factor Reviews, 2006

7. Core B: Image Fusion Gore Core C: Biomath & Bioinformatics Shyr Project 3: Bone metastasis Mundy Vanderbilt-Ingram Cancer Center Mouse Models of Human Cancer Consortium Vanderbilt Integrative Cancer Biology Center Prostate Center Center for Bone Biology VU Institute for Imaging Sciences Breast SPORE BioMathematics Small animal imaging Proteomics Core A: Protein collection & Proteomics Caprioli Biostatistics Project 1: Breast Cancer Moses Matrisian TGF  effectors Vanderbilt University Tumor Microenvironment Network VUTMEN Project 2: Prostate Cancer Hayward & Bhowmick

8. 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]

9. II. Tissue Recombination Experiments

10. 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

11. 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)

12. Mathematical modeling of epithelial-stromal interactions Modeling Goal How 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.

13. III. Two Step Model of Tumorigenesis

14. Two-Step Model of Tumorigenesis Experimental Observation 100% Normal  Normal 50/50 Mix  PIN & Invasion 100% Altered  PIN

15. Two-Step Model of Tumorigenesis Experimental Observation 100% Normal  Normal 50/50 Mix  PIN & Invasion 100% Altered  PIN Model Step 1: Normal  PIN Morphogen location: altered stroma Step 2: PIN  Invasive Morphogen location: altered stroma

16. Altered Stroma Normal Epithelium Proliferative Epithelium Invasive Epithelium HGF 1

17. Normal Stroma Normal Epithelium Proliferative Epithelium Invasive Epithelium SDF1 2

18. Normal Stroma Altered Stroma Normal Epithelium Proliferative Epithelium Invasive Epithelium HGF SDF 1 2

19. Normal Stroma Altered Stroma Normal Epithelium Proliferative Epithelium Invasive Epithelium HGF SDF 100% Normal  Normal Epithelium 2 1

20. Normal Stroma Altered Stroma Normal Epithelium Proliferative Epithelium Invasive Epithelium HGF SDF 100% Altered Stroma  Proliferative Epithelium 2 1

21. Normal Stroma Altered Stroma Normal Epithelium Proliferative Epithelium Invasive Epithelium HGF SDF 50% Altered Stroma  Invasive Epithelium 2 1

22. IV. Hybrid Computational Model

23. 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.

25. Hybrid Model Continuous, PDE Component Morphogen production, diffusion and decay is modeled with the heat equation. Production rates k 1, k 2 (s -1 ) Diffusion rates D 1, D 2 Decay rates k d1, k d2

26. Morphogen Concentrations

27. Simulation Results PIN Invasion

28. Phase Diagram: Transitions Depend Weakly on Production Levels

29. ‘Most Susceptible’ Epithelial Cells

30. 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).

31. Thank You