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The Leight lab seeks to understand how the extracellular matrix is remodeled during tumor progression and how this remodeling affects cancer cell function and treatment responsiveness. Towards this goal, we develop new methods and technologies to study the microenvironment. We have focused on two main areas of matrix remodeling, degradation by matrix metalloproteinases (MMPs) and changes in the physical properties of the matrix, such as stiffness and fiber organization.
Matrix metalloproteinase (MMP) expression is elevated in almost all tumor types, including breast, colon, pancreas, and melanoma, and increased expression is often correlated with decreased survival. However, it remains unclear specifically which enzymes (of the 20+ in the MMP family) are important at each stage of disease progression and how proteolysis is regulated in space and time. To investigate MMP activity, we develop new fluorescent biosensors and biomaterials to measure MMP activity in 3D cellular microenvironments. A critical barrier towards achieving this in-depth understanding of the regulation of MMPs is the lack of methods and culture systems to study MMP activity in situ. To overcome this barrier, the Leight lab has developed a unique approach in which 3D hydrogel cell culture platforms are functionalized with MMP fluorogenic substrates to enable measurement and visualization of MMP activity in space and time. We have also developed a new zymographic technique using the MMP fluorogenic substrates, which has given new insight into the specific proteases responsible for hydrogel degradation. Beyond cancer biology, this knowledge will aid in the rational design of resorbable biomaterials for applications such as drug delivery and regenerative medicine.
New studies in the lab are focused on using these fluorescent sensor functionalized hydrogels in other applications. We have developed and characterized a high throughput version of this system, and we are using this system for ex vivo culture of human tumor tissue, with future applications in drug screening and personalized medicine. The fluorogenic sensor can also be visualized using microscopy, and we are developing new image analysis programs to analyze the heterogeneity of MMP activity in a given cell population, and how that might change with different microenvironmental conditions or drug treatment.
In addition to matrix degradation, the Leight lab also studies the organization of ECM fibers in the tumor microenvironment. The ECM becomes organized and aligned during tumor progression and provides highways for invading tumor cells, yet the underlying mechanisms remain unclear. Leveraging the strength of OSU’s Comprehensive Cancer Center, we have led a collaborative effort to establish the role of the tumor suppressor phosphatase and tensin homolog (PTEN) in matrix alignment in a murine model and in breast cancer patients.
Visualizing matrix degradation
Reorganization of ECM fibers