Focal-adhesion-independent integrin-av regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion

Abstract

Integrins play crucial roles in epithelial adhesion, proliferation, wound healing and cancer. In the epidermis, the roles of many integrin subunits are incompletely defined and mechanistic details regarding their functions are lacking. We performed a multiplexed small hairpin (sh)RNA screen to define roles for each subunit in human organotypic skin. We show that integrin-αv (also known as ITGAV) heterodimers are essential for epidermal generation, with integrin-αv loss driving a keratinocyte G1-S cell cycle block. Surprisingly, integrin αv is not localized within keratinocyte focal adhesions, and instead maintains proliferation by controlling cellular (c)-Myc translation through FAK, p38β and p90RSK1. These phenotypes depend only on the binding partners of integrin-αv - integrin β5 and integrin β6 (also known as ITGB5 and ITGB6, respectively). Through inducible depletion of integrin αv in both normal organotypic epidermis and Ras-driven invasive neoplasia, we show that integrin αv is required for de novo tissue generation and neoplastic invasion but that it is dispensable for epidermal maintenance. Heterodimers of integrin αv with integrin β5 (integrin αvβ5) or integrin β6 (integrin αvβ6) are required to similar extents for neoplastic invasion, thus identifying integrin αvβ5 and integrin αvβ6 heterodimers as potential therapeutic targets for epidermal squamous cell carcinoma.