Developing 3D Engineered in Vitro Models to Study the Impact of Brain Microenvironment Derived Cues and Chemotherapy Drugs on Dormancy in Brain Metastatic Breast Cancer

Breast cancer cells are known to disseminate to distant organs (brain, liver, lungs, bone, and lymphnodes) to develop secondary (metastatic) tumors. Upon arriving in the secondary organ, disseminated tumor cells (DTCs) exhibit dormancy to evade cell death and gain therapeutic resistance via tumor microenvironment-derived biomechanical, cellular and/or bio-chemical cues. Metastatic breast cancers are considered to be incurable with a dismal 5-year survival rate of only 27%. Among breast cancer metastasis, breast cancer brain metastasis (BCBM) is very aggressive with a median survival rate of 15 months. A mechanistic understanding of tumor cell-brain microenvironment interactions involved in attaining a dormant state in BCBM cells is crucial inidentifying new therapeutic targets for BCBM. This dissertation focuses on studying the impact of extracellular matrix derived cues, cellular cues and chemotherapy drugs on BCBM dormancy. Specifically, hyaluronic acid (HA) hydrogels with matrix stiffness comparable to both native brain and brain metastatic niche were utilized to study the impact of biomechanical cues on tumor dormancy in BCBM cell clusters (spheroids). The impact of spheroid size on tumor dormancy was also studied. In addition, this hydrogel system was employed to study regulation of tumor mass dormancy in BCBM spheroids. Further, impact of a chemotherapeutic drug (Paclitaxel) on BCBM dormancy was studied. Finally, HA hydrogel based dormancy model was utilized to study the impact of cellular cues on theregulation of BCBM dormancy, by co-culturing dormant BCBM cells with astrocytes. Taken together, the development of such models is poised to provide key scientific insights into the mechanisms involved in BCBM dormancy.