The epidermal integrin-mediated secretome regulates the skin microenvironment during tumorigenesis and repair.

• Integrins are transmembrane receptors for extracellular matrix adhesion. • Keratinocyte integrins regulate factors such as matrix proteins, proteases, growth factors, and cytokines that are secreted into the microenvironment (i.e., the secretome). • Integrin α3β1 is emerging as a regulator of the secretome in keratinocytes. • Integrin-regulated secreted factors mediate crosstalk to the microenvironment by: (1) promoting matrix generation through the regulation of ECM/BM proteins, (2) promoting matrix remodeling through the regulation of proteases, or (3) supporting stromal cells through the regulation of cytokines and/or growth factors. • Secreted factors regulated by certain integrins can promote paracrine crosstalk to distinct cells such as immune cells, endothelial cells, and fibroblasts to control both pathological (i.e., tumor growth and progression) and repair (i.e., wound healing) processes. Integrins are cellular transmembrane receptors that physically connect the cytoskeleton with the extracellular matrix. As such, they are positioned to mediate cellular responses to microenvironmental cues. Importantly, integrins also regulate their own microenvironment through secreted factors, also known as the integrin-mediated secretome. Epidermal integrins, or integrins expressed by keratinocytes of the skin epidermis, regulate the cutaneous microenvironment through the contribution of matrix components, via proteolytic matrix remodeling, or by mediating factors like cytokines and growth factors that can promote support for nearby but distinct cells of the stroma, such as immune cells, endothelial cells, and fibroblasts. This role for integrins is enhanced during both pathological and repair tissue remodeling processes, such as tumor growth and progression and wound healing. This review will discuss examples of how the epithelial integrin-mediated secretome can regulate the tissue microenvironment. Although different epithelial integrins in various contexts will be explored, emphasis will be given to epidermal integrins that regulate the secretome during wound healing and cutaneous tumor progression. Epidermal integrin α3β1 is of particular focus as well, since this integrin has been revealed as a key regulator of the keratinocyte secretome. [ABSTRACT FROM AUTHOR]