The role of mechanics in tumor progression and malignancy

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DESCRIPTION (provided by applicant): The role of mechanics in tumor progression and malignancy over the last few decades, various studies have converged upon the idea that the microenvironment is important in the progression of cancer. Specifically, the normal interactions with the microenvironment can suppress tumor formation and growth, while disruption of the normal context can support the progression and metastasis of tumors. More recent studies have suggested that the mechanical properties of the microenvironment plays an important role in this interaction, but the mechanism by which cells sense the mechanics of the environment, and how this interaction is altered in cancer remains unknown. In this project, we will investigate the effect of mechanics of the microenvironment on mammary epithelial cell proliferation, migration, and malignancy in reconstituted three dimensional alginate gel matrices. Precise control over viscoelasticity and legend density is possible with alginate gels, and a technique to precisely measure the number of bonds cells form with the gel has been established. We will probe the effect of matrix elasticity, viscoelasticity, and ligand density on proliferation and migration of the non-malignant mammary epithelial cells, and see how this response changes for pre-malignant and malignant mammary epithelial cells. Then we will develop a technique to measure strains and stresses exerted by the cells on the alginate gels, and use these measurements to elucidate the mechanism by which the cells physically probe their microenvironment. These measurements will also be conducted across cell lines with different malignant phenotypes to determine whether differences in this mechanism are correlated with different sensitivities to the microenvironment. The experiments proposed here will provide general insight into the nature of cancer malignancy as well as the mechanism by which cells sense their mechanical microenvironment. Such insight could be relevant for diagnosis of cancer malignancy, and suggest new techniques for suppressing tumor progression and malignancy.