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Title: “Impact of Tumor Microenvironment on Intracellular Properties within a 3D System” Committee: Dr. Muhammad Zaman, BU BME (Advisor) Dr. Darren Roblyer, BU BME (Chair) Dr. Katherine Zhang, BU ME Dr. Xaralabos Varelas, BU Biochemistry Dr. Michael Mak, Yale BME Abstract: Breast cancer remains one of the leading causes of cancer death in women with one in eight women expected to develop breast cancer. Breast cancer progression causes several adverse changes in the extracellular matrix (ECM) composition and organization including an increase in stromal collagen and stiffening of the ECM. Clinical studies have recently discovered that stiff and dense breast tissue, a result of the abnormal architecture of the tumor microenvironment, correlates with breast tumor growth and increases the likelihood of tumor metastasis. However, the tumor microenvironment influence on cancer progression and intracellular behavior is not well understood due to the lack of physiologically relevant three dimensional (3D) in vitro models that are able to capture the mechanical and structural in vivo complexity and are also able to provide rigorous and quantitative understanding. The goal of this dissertation is to investigate how the mechanical components of the microenvironment influence intracellular and molecular activity to drive cancer progression in a robust and scalable 3D system. In order to address these gaps, our work studied the impact of collagen concentration, cell type, and drug incubation time on drug response in 2D and 3D environments. To understand the role of local cellular mechanics in mediating drug response, we optimized and utilized particle-tracking microrheology to quantify the intracellular activity of single cells and spheroids embedded in 3D collagen gels. Finally, our study connected both structure and mechanics with cell signaling by investigating the relationship between the mechanical components of the ECM and the YAP/TAZ pathway. Furthermore, we integrated our 3D embedded spheroid model with tissue clearing methods to allow for complete visualization of YAP/YAZ activity throughout the dense spheroid structure. Collectively, the results showed that matrix properties interact with matrix dimensionality to influence drug response. This interaction also was found to affect intracellular activity, even in the presence of chemotherapeutic and anti-MMP drugs. We then showed how this interaction in mechanics and ECM properties affects the spatial and temporal heterogeneity of YAP/YAZ activity within a 3D spheroid. Overall, the work in this dissertation provides new insights into how the physical properties of the tumor microenvironment influence cellular form and function, as well as response to therapy of cancer cells, which may have implications on development of novel treatment strategies and patient outcome.