In many pathological and physiological settings, cells must integrate numerous signals from their environment. Often times, these signals are spatially inhomogeneous and are presented in the form of gradients or asymmetric structures like aligned fibers. For instance, cancer cells must interpret both chemotactic and contact guidance cues in the tumor microenvironment. While thousands of studies have examined how individual directional cues influence migration, relatively few have examined how cells respond to simultaneously presented directional cues. Furthermore, while there is an appreciation that 3D environments more closely match the in vivo tumor microenvironment, it is not clear which aspect of 3D environments (topology, confinement or mechanical properties) regulates directed migration, particularly in the context of multi-cue sensing.
In this talk, I will discuss the competition and cooperation of chemotactic and contact guidance cues in directing cancer cell migration. We employ several different techniques to generate gradients of growth factors and aligned extracellular matrix structures, inducing chemotaxis and contact guidance, respectively. We have also developed hybrid environments that allow us to present contact guidance cues while tuning topology, confinement and mechanical properties. These hybrid environments show dramatic differences in the ability of contact guidance cues to direct migration. For instance, environments where MDA-MB-231 breast cancer cells contact aligned collagen fibrils with both ventral and dorsal surfaces are more directional than cells migrating on 2D surfaces. In 2D multi-cue environments, we observe that gradients of epidermal growth factor (EGF), a known chemoattractant, can enhance the directionality of cells migrating in response to contact guidance cues when presented parallel to the contact guidance cue. However, when presented perpendicular to the contact guidance cue, directionality is unchanged. Understanding how different cues compete or cooperate to direct migration as well as how topology, confinement and mechanical properties alter competition and cooperation is critical in understanding how cancer cells sense and respond to the tumor microenvironment. In addition, these multi-cue environments could be designed to be used to separate subpopulations of highly invasive cancer cells or to screen chemotherapies that block invasion.
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