| dc.description.abstract | Breast cancer is the second-highest cancer occurrence in women in the United States and is the most prevalent cancer worldwide, with many studies dedicated to understanding its characteristics. In addition to examining tumor cells, investigations have delved into the tumor microenvironment. Tumor stroma has been shown to regulate cell behaviors through mechanical and chemical cues. Significantly, ECM stiffening has been linked to increased tumor metastatic potential. Despite advancements made in recent years, many questions remain regarding how matrix stiffness influences tumor vasculature and each step of tumor metastasis, especially intravasation.
In this dissertation, I explore the effects of matrix stiffness on tumor microenvironment and tumor vasculature function. My findings indicate that matrix stiffness undermines endothelial barrier function by activating focal adhesion kinase. Furthermore, matrix stiffness promotes cancer-macrophage interactions and the accumulation of M2-like macrophages by increasing CSF-1 secretion from tumor cells. I also demonstrate that matrix stiffness facilitates tumor cell intravasation by promoting enhanced expression and ESRP1-mediated alternative splicing of MENA. Additionally, I adapted the quantitative polarization microscope to assess cell contractility, which is a critical cellular response to alterations in tissue mechanical properties, I adapted quantitative polarization microscopy. This allows for the precise quantification of cell contractility across two-dimensional and three-dimensional cell cultures and within tissue samples. Considering the link between breast cancer and diabetes, particularly how sugars stiffen the matrix via glycation, I then examined the effects of hyperglycemia-mediated glycation on the interplay between diabetes and breast cancer. I discovered that hyperglycemia exacerbates tumor growth, ECM stiffness, and EMT of tumor cells via activating glycation. Furthermore, I found that glycation-induced ECM stiffening and activated AGE-RAGE signaling result in increased contractility, NF-κB activation, GM-CSF secretion in tumor cells, and impaired tumor vasculature barrier function.
This work deepens our understanding of how the mechanical properties of tumor ECM influence the behavior of various cell types within tumors and overall tumor progression. These findings suggest that mechanical cues may serve as a potential link between cancer and other diseases. | |
