Integrin α3β1 on Tumor Keratinocytes Is Essential to Maintain Tumor Growth and Promotes a Tumor-Supportive Keratinocyte Secretome

The development of integrin-targeted cancer therapies is hindered by incomplete understanding of integrin function in tumor cells and the tumor microenvironment. Previous studies showed that mice with epidermis-specific deletion of the alpha 3 integrin subunit fail to form skin tumors during two-step chemical tumorigenesis, indicating a protumorigenic role for integrin alpha 3 beta 1. Here, we generated mice with tamoxifen-inducible, epidermis-specific alpha 3 knockout to determine the role of alpha 3 beta 1 in the maintenance of established tumor cells and/or the associated stroma. Genetic ablation of alpha 3 in established skin tumors caused their rapid regression, indicating that alpha 3 beta 1 is essential to maintain tumor growth. Although reduced proliferation and increased apoptosis were observed in alpha 3 beta 1-deficient tumor cells, these changes followed a robust increase in stromal apoptosis. Furthermore, macrophages and fibulin-2 levels were reduced in stroma following alpha 3 deletion from tumor cells. Mass spectrometric analysis of conditioned medium from immortalized keratinocytes showed that alpha 3 beta 1 regulates a substantial fraction of the keratinocyte secretome, including fibulin-2 and macrophage CSF1; RNA in situ hybridization showed that expression of these two genes was reduced in tumor keratinocytes in vivo. Our findings identify alpha 3 beta 1 as a regulator of the keratinocyte secretome and skin tumor microenvironment and as a potential therapeutic target.