Cancer is a major cause of death in the United States. Although uncontrolled cell division is a hallmark of tumor formation, the spread of cancer cells from a primary tumor to other organs, i.e. metastasis, is the key feature that leads to high mortality rates. During metastasis, epithelial cancer cells detach from the primary tumor site and acquire a highly motile and/or mesenchymal phenotype. Migration/invasion of these cells into surrounding tissue and the circulatory/lymphatic system leads to colonization of distal tissues and secondary tumor formation. The central biological mechanism responsible for metastasis is known as epithelial to mesenchymal transition (EMT). In addition to its role in cancer metastasis, EMT is a fundamental biological process that plays an important role in embryonic development, wound healing and organ fibrosis. During EMT polarized epithelial cells undergo dramatic biochemical and biostructural changes and acquire a mesenchymal phenotype with enhanced migratory and invasive capacity. Although many of the biochemical signaling events that occur during oncogenic EMT are known, the biomechanical mechanisms governing oncogenic EMT are not well established. Furthermore, although it is well established that the tumor microenvironment can influence cancer progression and that increased tumor stiffness is a diagnostic indicator of advanced disease, there is limited information about how changes in the tumor?s biomechanical properties (i.e. matrix stiffness) influence EMT and metastatic potential.
This proposal utilizes a combination of biophysical, molecular biology and quantitative engineering tools to investigate the biomechanical mechanisms governing oncogenic EMT and to investigate how changes tissue/matrix mechanics influences EMT and metastasis. Sophisticated experimental techniques will be used to characterize changes in cellular mechanics during EMT in different cancer cells. Several biomechanical markers of EMT (i.e. stiffness, viscoelasticity and contractility) will be correlated with cell migration and invasion behaviors. In addition to establishing a unique set of biomechanical markers of EMT, these studies will also provide an innovative way to quantitatively assess metastatic potential based on the cell's mechanical phenotype. Experimental techniques will also be used to investigate how changes in substrate/matrix stiffness influence the biomechanical and biochemical signaling mechanisms responsible for oncogenic EMT. Finally, three-dimensional multi-scale computational models of tumor cell detachment and migration/invasion will be developed and these computational models will be used to develop new insights into how changes in cell mechanics may be used to mitigate metastasis. The proposed research studies will provide training for a post-doctoral research scientist and undergraduate/graduate students in biomedical engineering at The Ohio State University and will also be integrated into an undergraduate course in quantitative physiology. Outreach activities included contributing to a summer educational program for high school students in computational modeling hosted by the Ohio Supercomputer Center.
