(776b) Engineered Microenvironments to Analyze Host-Tumor Cell Interactions

The development of normal tissues, both natural and engineered, requires concerted interactions between  cells and their local microenvironment.  Similarly, breast tumor development is modulated by cues from the surrounding microenvironment, including interactions with neighboring non-tumor cells as well as the extracellular matrix (ECM).  In addition to chemical signals, studies using homogeneous populations of breast cancer cell lines cultured in three-dimensional (3D) ECM have shown that the physical properties of the microenvironment, namely increased ECM stiffness, can stimulate the invasion of tumor cells.  However, at early stages of breast cancer development, malignant cells are surrounded by normal epithelial cells, which have been shown to have a tumor-suppressive effect on co-cultured cancer cells.  Here we used tissue engineering strategies to explore how the biophysical characteristics of the host microenvironment affect the proliferative and invasive tumor phenotype of the earliest stages of tumor development.  We used a 3D microfabrication-based approach to engineer ducts comprised of normal mammary epithelial cells that contained a single tumor cell.  We found that tumor cell phenotype was dictated by position in the duct, as tumor cell proliferation and invasion were enhanced at the ends, while these effects were blocked when the tumor cell was located elsewhere.  Regions of invasion correspond  with regions of 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 confirmed that regions of high mechanical stress correspond with 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.  Our study also suggests that tissue engineering strategies can be used to unveil novel aspects of tumor development.