| Breast tumor development is regulated in part by cues from the local microenvironment, including interactions with neighboring non-tumor cells as well as the extracellular matrix. This thesis explores how characteristics of the host microenvironment affect tumor phenotype at the earliest stages of tumor development by using a 3D microfabrication-based approach to engineer ducts comprised of normal and tumorigenic mammary epithelial cells, and agent-based modeling implemented through the CompuCell3D framework.;Experimentally, we found that the phenotype of the tumor cell was dictated by its position in the duct: proliferation and invasion were enhanced at the ends and blocked when the tumor cell was located elsewhere within the tissue. Regions of invasion correlated with high endogenous mechanical stress, as shown by finite element modeling and bead displacement experiments, and modulating the contractility of the host epithelium controlled the subsequent invasion of tumor cells. Combining micro-computed tomographic analysis with finite element modeling suggested that predicted regions of high mechanical stress correspond to regions of tumor formation in vivo. This work suggests that the mechanical tone of the non-tumorigenic host epithelium directs the phenotype of tumor cells, and provides additional insight into the instructive role of the mechanical tumor microenvironment.;Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer resulting from abnormal proliferation of mammary epithelial cells. Computationally, we explored the conditions leading to the development of the four morphologies of DCIS using a two-dimensional agent-based model. We found that relative rates of cell proliferation and death governed which of the four morphologies emerged. The natural progression between morphologies cannot be investigated in vivo; however, our model suggests probable transitions between these morphologies during breast cancer progression. Motivated by our experimental studies, we extended our model from a circular geometry to more physiologically relevant geometries. Again we found that cells are more likely to invade from the end of ducts and that this preferential invasion can be modulated by altering cell adhesion or contractility. This preliminary model provides us with additional insight into tumor cell behavior and allows us to explore behavior not readily monitored in vivo.. |
