| First Author | Longmate WM | Year | 2021 |
| Journal | J Invest Dermatol | Volume | 141 |
| Issue | 1 | Pages | 142-151.e6 |
| PubMed ID | 32454065 | Mgi Jnum | J:300327 |
| Mgi Id | MGI:6491515 | Doi | 10.1016/j.jid.2020.05.080 |
| Citation | Longmate WM, et al. (2021) Integrin alpha3beta1 on Tumor Keratinocytes Is Essential to Maintain Tumor Growth and Promotes a Tumor-Supportive Keratinocyte Secretome. J Invest Dermatol 141(1):142-151.e6 |
| abstractText | 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 alpha3 integrin subunit fail to form skin tumors during two-step chemical tumorigenesis, indicating a protumorigenic role for integrin alpha3beta1. Here, we generated mice with tamoxifen-inducible, epidermis-specific alpha3 knockout to determine the role of alpha3beta1 in the maintenance of established tumor cells and/or the associated stroma. Genetic ablation of alpha3 in established skin tumors caused their rapid regression, indicating that alpha3beta1 is essential to maintain tumor growth. Although reduced proliferation and increased apoptosis were observed in alpha3beta1-deficient tumor cells, these changes followed a robust increase in stromal apoptosis. Furthermore, macrophages and fibulin-2 levels were reduced in stroma following alpha3 deletion from tumor cells. Mass spectrometric analysis of conditioned medium from immortalized keratinocytes showed that alpha3beta1 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 alpha3beta1 as a regulator of the keratinocyte secretome and skin tumor microenvironment and as a potential therapeutic target. |
