Competition Between Contractility and Surface Tension in Collective Cell Migration

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Biological cells migrate in groups both during healthy life and also during diseases during tissue changes ranging from wound repair to cancer progression. The migration can restore normal function of damaged tissue, as in wound repair, or further the spread of disease, as in a spreading cancer. In both wound healing and cancer, it is typical for cells to migrate together where each cell's motion depends its own active contractile forces and its interaction with neighbors. The resulting cellular motions can vary dramatically--from a solid-like state, where each cell remains close to its neighbors, to a fluid-like state, where each cell freely migrates past its neighbors. The transition between solid-like and fluid-like migration occurs in both wound healing and cancer invasion and its causes remain unclear. Theoretical models have predicted that the transition depends on the adhesion molecules between neighboring cells, and, counterintuitively, that greater adhesion causes a more fluid-like behavior. This prediction is complicated by the fact that some molecules associated with cell-cell adhesion also cause cells to contract and pull against their neighbors. The work will experimentally examine the competing roles of adhesion and contraction on collective migration, thereby clarifying our understanding of collective migration and providing new insights into how the migration may be promoted in wound healing or reduced during cancer progression. The PI will recruit undergraduate students from underrepresented groups in science and engineering through the Summer Undergraduate Research Experience (SURE) program in the College of Engineering at UW-Madison. Through the SURE program, these students will gain research experience and will be encouraged to pursue graduate studies.This research will test the hypothesis that the solid-to-fluid transition results from a balance between the active contractile tension inside each cell and the adhesive surface energy at each cell-cell interface. To quantify intercellular adhesion, this project will use a mechanically rigorous definition, the surface tension. To quantify contraction, it will use the contractile stress within each cell. Surface tension and contractile stress will be modulated by using pharmacological inhibitors and transfections of appropriate signaling pathways, and they will be measured by using state-of-the art optical microscopy and quantitative image analysis. The first objective of this research will reveal how the intracellular surface tension results from the balance between the actomyosin contraction in each cell's cortex and the adherens junctions at each cell-cell interface. The second objective will investigate how contractility and surface tension together regulate the multicellular motion. The resulting data will give a complete account of the mechanics of collective cellular motion, and thus they will provide an empirical basis for testing theories for the mechanisms of collective migration.