CAREER: Connecting Physical Forces to Cell Migration Through Complex Environments

Cells in our bodies migrate to repair wounds, fight infections, and build tissues. When these movements go awry, they contribute to diseases such as cancer metastasis, fibrosis, and chronic infection. To move efficiently, cells must push, pull, and squeeze their way through a complex three-dimensional environment filled with tiny pores and physical obstacles. This Faculty Early Career Development Program (CAREER) project seeks to understand how cells generate and coordinate the physical forces needed to navigate through tight spaces and to determine how these abilities vary across different environments and cell types. By revealing the mechanical rules that govern cellular movement, this research will inform future strategies to enhance tissue repair, limit cancer spread and guide the design of biomaterials and therapeutics. This research project will define the force-generation strategies that different types of cells use to migrate through confined 3D microenvironments with varying geometries and mechanical properties. To do so, we will develop the technologies to precisely pattern biomaterials at sub-cellular length scales and couple these approaches with advanced microscopy and machine learning to quantify the magnitude, direction, and timing of cell-generated forces. With these tools, we will experimentally test competing mechanistic models of propulsion during confined migration. Additionally, we will utilize molecular tension sensors to visualize how forces propagate inside cells and to map the biochemical signaling pathways that regulate movement through constrictions. These combined measurements will identify the mechanical design principles that allow cells to sense, respond to, and select propulsion modes in different tissue environments. The resulting insights will advance core knowledge in biomechanics and mechanobiology while providing broadly accessible tools for the research community to quantify force transmission and transduction during cell migration. 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. NSF Award ID: 2540625 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Wesley Legant | Institution: University of North Carolina at Chapel Hill, CHAPEL HILL, NC | Award Amount: $615,000 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2540625 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2540625.html