CAREER: Mechanobiology of Mesenchymal-Epithelial Transition

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When cells are weakly attached to each other, they are able to migrate. This happens when cancer spreads, but also when an embryo grows. Whether cells can change from ones that move into ones that remain in the same place is partly dependent on the tissue stiffness. If we better understand this change in cells, it will improve our understanding of how cancer progresses and how our organs grow. The change from mobile to a static cells is call mesenchymal-epithelial transition (MET). MET is important to kidney and heart development, wound healing and cancer metastasis. When MET happens, migrating cells change so that they are immobile and tightly bound to neighboring cells. MET depends on tissue stiffness, but the details of the dependence aren't known. This Faculty Early Career Development Program (CAREER) project will measure the response of cells to dynamic changes in matrix stiffness and determine how EMT is affected by tissue stiffness. This will help in understanding how embryos grow, how to better manufacture artificial tissues and in building 'organs on a chip' that can be used for drug discovery research. The PI and graduate student supported through this project will develop and implement a workshop for grade 6-12 teachers focused on biomechanics and mechanobiology concepts so that they can better teach their students, including how engineering research impacts society. Mesenchymal-epithelial transition (MET) is a phenotypic change in which migratory cells with weak cell-cell contacts transition to tightly bound cells exhibiting apical-basal polarity. MET is central to embryonic remodeling, establishment of organ architecture, wound healing, reprogramming of somatic cells into induced pluripotent stem cells, and metastatic dissemination of cancer cells. While it is recognized that mechanical properties of the cellular niche change dynamically during MET-associated processes in vivo, important questions still remain regarding how microenvironmental physical properties regulate MET. The goal of this CAREER project is to develop a dynamic hydrogel system that recapitulates changes in tissue mechanical properties during MET-associated events, and then to use this system to determine the expression of genes associated with epithelial and mesenchymal phenotypes, cytoskeletal remodeling, and cell migration. Further studies will elucidate the role of key mechanoresponsive signaling molecules and epigenetic remodeling in regulating MET response to mechanical signals. The establishment of molecular mechanisms linking tissue mechanics and MET will result in a better understanding of mechanotransduction processes and will provide insight into how mechanical signals regulate cell plasticity. The research program provides the foundation for educational and outreach efforts aimed toward incorporating positive themes about the impact of engineering and mechanobiology on society into engineering curricula and into recruitment efforts directed toward grade 6-12 through graduate-level students. A workshop for grade 6-12 teachers focused on biomechanics and mechanobiology concepts will be developed and implemented and will demonstrate how research impacts society.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.