Dry and moist skin (e.g., in the mouth) plays a critical role in maintaining a barrier against environmental insults and cancer. Based on new data, this team believes that individuals with FA may have an impaired barrier and this may be why they are at risk for SCC. Specifically, data shows that FA pathway loss impairs adhesion between skin cells. FA pathway loss also stimulates motility in cells that would otherwise be stationary; this is particularly interesting, given that cancer cells have reduced attachments to their environment and tend to be highly motile. Moreover, the link between the FA pathway and changes in the skin may be due to altered lipid levels and Rac1 signaling. Fortunately, it is possible to restore lipid levels and signaling to normal with existing drugs and in this proposal it will be determined if this can normalize skin architecture to prevent and treat FA SCC.