Cell Migration Control through Modulation of Multiple Directional Cues

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ABSTRACT The goal of this project is to use engineered extracellular matrix environments leveraging structural and me- chanical control over the extracellular matrix to examine the mechanisms by which cells respond to multiple directional migration cues. Cell migration plays an important role in many physiological and pathological pro- cesses such as wound healing, development and cancer invasion. Frequently migration is not simply random, but directed towards targets through recognition of aligned extracellular matrix fibers or gradients in stiffness, generating contact guidance and durotaxis, respectively. In many biological contexts these cues are presented simultaneously, forcing cells to integrate this information. For instance, gradients of stiffness and aligned colla- gen are generated within the wound bed to direct dermal fibroblast migration. Similar fiber structures and gra- dients stimulate cancer cell migration out of the tumor microenvironment and normal cells including stromal and immune cells towards the tumor microenvironment. While there is a firm understanding of how cells re- spond to individual directional cues, virtually nothing is known about how cells integrate multiple cues and make migrational decisions based on that integration. Furthermore, there is a hypothesis that contact guidance and durotaxis are overlapping directional cell migration mechanisms, but this has not been rigorously tested. Mechanistic understanding of multi-cue directional migration will require a refined understanding of how the F- actin and microtubule networks operates. Indeed, some evidence suggests that contact guidance and durotax- is may use slightly different F-actin network structures, since contact guidance is thought to be governed by F- actin fiber structures, but durotaxis is not. Engineering approaches will be taken to design in vitro environments that allow for independent tuning of contact guidance and durotaxis in both 2D and 3D environments. Further- more, the effect of F-actin branching, bundling and contraction in allowing cells to prefer aligned fibers of colla- gen or gradients of stiffness will be tested. This will uncover shared or competing molecular pathways involved when these two directional migration cues are present in isolation and together. Understanding how cells mi- grate in response to multiple cues has broad impact on several biomedical fields including tissue engineering and disease therapeutics. Determining how cells respond to multiple cues in vitro will allow us to predict cell responses in wound healing, development, cancer invasion and immune response leading to drug candidates as in cancer or strategies to enhance wound healing and immune response.