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

• Published in: Journal of investigative dermatology Vol. 141; no. 1; pp. 142 - 151.e6
• Main Authors: Longmate, Whitney M., Varney, Scott, Power, Derek, Miskin, Rakshitha Pandulal, Anderson, Karl E., DeFreest, Lori, Van De Water, Livingston, DiPersio, C. Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021
• Subjects: Animals; Apoptosis; Cell Adhesion; Cell Movement; Epidermis - metabolism; Epidermis - pathology; Humans; Integrin alpha3beta1 - metabolism; Keratinocytes - metabolism; Keratinocytes - pathology; Mice; Mice, Knockout; Neoplasms, Experimental; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; SCC; TMK; IMK; MS; GSEA; TME; ECM; MK; 4OHT
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1016/j.jid.2020.05.080

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 α3 integrin subunit fail to form skin tumors during two-step chemical tumorigenesis, indicating a protumorigenic role for integrin α3β1. Here, we generated mice with tamoxifen-inducible, epidermis-specific α3 knockout to determine the role of α3β1 in the maintenance of established tumor cells and/or the associated stroma. Genetic ablation of α3 in established skin tumors caused their rapid regression, indicating that α3β1 is essential to maintain tumor growth. Although reduced proliferation and increased apoptosis were observed in α3β1-deficient tumor cells, these changes followed a robust increase in stromal apoptosis. Furthermore, macrophages and fibulin-2 levels were reduced in stroma following α3 deletion from tumor cells. Mass spectrometric analysis of conditioned medium from immortalized keratinocytes showed that α3β1 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 α3β1 as a regulator of the keratinocyte secretome and skin tumor microenvironment and as a potential therapeutic target.