The Role of Matrix Stiffness in the Regulation of Matrix Metalloproteinase Activity

College of Engineering Undergraduate Research ScholarshipMatrix metalloproteinases (MMPs) are a family of proteolytic enzymes that enable cell-mediated remodeling of the tumor microenvironment. MMP levels have been found to be upregulated in almost all tumor types and have been shown to play a critical role in extracellular matrix remodeling, basement membrane penetration, and eventually, tumor metastasis. It has been shown that matrix stiffness increases with tumor progression, however, it has yet to be elucidated how mechanical cues from the microenvironment such as matrix stiffness work to regulate MMP activity and how this activity is spatially distributed. Recently, a mouse model has been developed which recapitulates the malignant transformation of mammary epithelial tumors attributed to increased collagen and extracellular matrix (ECM) deposition by stromal fibroblasts which is associated with increased tumor incidence and load. We hypothesized that the increased matrix stiffness associated with tumor progression will enhance MMP activity of stromal fibroblasts. To investigate this hypothesis, we utilized a poly(ethylene glycol) hydrogel system functionalized with a fluorogenic MMP sensor to pursue two aims: 1) visualization and quantification of in situ MMP activity in murine mammary tumors and 2) encapsulation of isolated fibroblasts in hydrogels with precisely tuned stiffness. Results investigating the effect of matrix stiffness on MMP activity of isolated fibroblasts indicate no significant relationship due to large variability between experiments. In situ zymography experiments showed specific localization of MMP activity on tissues that can be localized to specific cell types when combined with immunohistochemistry. A better understanding of the underlying mechanisms of the tumor microenvironment will help lead to more effective cancer therapeutics.No embargoAcademic Major: Biomedical Engineerin