Shuttling and function of MMP28 during EMT and collective migration

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PROJECT SUMMARY Matrix Metalloproteinase (MMPs) constitute a family of proteases primarily known for their matrix remodeling activity in several cancers and chronic inflammatory diseases. However, MMPs are also found in intracellular compartments including the nucleus of several cell types. MMP28 is the last identified member of the family, it is involved in wound repair, central nervous system development, and immune system maturation. In addition, MMP28 mis-regulation has been linked to several cancers. MMP28 activity can induce epithelial-to- mesenchymal transition (EMT) and migration in human alveolar epithelium where it has been described in the cell nucleus. Very little is known about the nuclear activity of MMPs or how MMPs are shuttling through different cellular compartments. In Xenopus laevis embryos, MMP28 is expressed in cranial placodes which are located lateral to the very motile neural crest (NC) cells, and later persists in the epibranchial placodes between the migrating streams of cranial NC cells. Interestingly, our preliminary results show that MMP28 secreted by cranial placodes is detected in the nuclei of neighboring NC cells. MMP28 knockdown experiments demonstrate that nuclear MMP28 activity is essential to trigger EMT and NC collective cell migration both in vivo and in vitro. The discovery of this non-canonical/nuclear activity of MMP28 is paradigm shifting in the MMP field. However, it is still unclear whether MMP28 function in the NC is restricted to this nuclear activity and whether MMP28 has a more conventional activity as well. Furthermore, the mechanisms by which MMP28 is internalized by NC cells and eventually shuttles to the nucleus are not known. In this application we propose to address these questions by, i) assessing how MMP28 modulates EMT and NC cells migration, and impacts the coordinated collective migration of both placode and NC cells; ii) uncovering the mechanisms controlling MMP28 trafficking from the extracellular compartment into the nucleus. The project has the strong potential to reveal novel aspects of MMPs functions, and their roles in the control of migratory cell behaviour in normal and pathological situations.