Understanding ECM Remodeling and Signaling in Breast Tumor Progression and Therapy Response

Breast cancer is the second leading cause of cancer-related death among women in the United States. While the five-year survival rate of premetastatic tumors is high, nearly 90%, this plummets to 27% once metastasis is detected within a distant organ, underscoring a pressing unmet clinical need to prevent and treat metastatic breast cancer. Excessive extracellular matrix (ECM) deposition and remodeling occurs alongside breast tumor progression and has been directly implicated in facilitating breast tumor metastasis. However, many of the mechanisms by which tumor-associated ECM remodeling promotes metastasis are unclear. This thesis addresses this knowledge gap from multiple angles, clarifying prometastatic mechanisms of biochemical and biomechanical ECM signaling as well as in-depth characterization of the causes and nature of pathological ECM remodeling in breast cancer. This research utilizes techniques across a spectrum of length scales including in vitro cell culture manipulations, orthotopic and genetically engineered mouse models, and human patient samples to establish robust, clinically relevant findings. First, this thesis examines the role of collagen-discoidin domain receptor 1 (DDR1) signaling and shows that DDR1 expression may play an important role dictating mammary epithelial differentiation and loss of DDR1 signaling may in part explain how highly aggressive, basal-like tumors form. The next chapter characterizes collagen remodeling in human breast tumors and shows triple negative tumors are particularly enriched for collagen crosslinks. Manipulations in mice suggest stromal cells primarily drive collagen crosslinking, and infiltrating macrophages activate stromal cells in the early stages of tumor development. Moreover, we identify stromal lysyl hydroxylase 2, the enzyme responsible for the formation of high valency collagen crosslinks found in rigid and fibrotic tissues, as a predictor of poor survival and a potentially useful biomarker to stratify patients for therapy. The following chapter examines how ECM stiffness in triple negative breast cancer influences therapy response. We demonstrate that treatment resistant residual disease occupies a soft ECM niche and that a compliant matrix tunes the NF-κB – JNK signaling axis to promote cell survival upon administration of apoptosis-inducing therapeutics such as chemotherapy and radiation. Finally, we explore the relationship between ECM stiffness and prometastatic tumor immunity. Collectively, these findings advance our understanding of mechanisms that promote breast tumor metastasis and provide considerable insights to inform the development of effective therapeutic strategies to prevent and treat metastatic disease