Abstract 2879: Expression of Focal Adhesion Kinase (FAK) in myeloid lineage cells increases with maturation and regulates primary tumor growth in MMTV-PyVmT murine model of breast cancer.

Myeloid lineage cells are critical mediators of innate immunity that contribute to the inflammatory environment associated with tumor formation and progression. Our research explores the role of adhesion signaling through Focal Adhesion Kinase (FAK) in myeloid lineage cells as a potential regulator of breast tumor outgrowth. Previously, we have demonstrated that recruitment of cd11b-positive monocytes to sites of thioglycollate-induced inflammation was impaired in the absence of FAK. Additionally, we showed that bone marrow-derived macrophages exhibit reduced migration toward chemotactic factors commonly found in the breast tumor milieu. Given these results, the goal of the current study is to address the fundamental contribution of FAK toward myeloid cell functions that regulate breast tumor growth and progression. Mice with FAK conditionally deleted in myeloid lineage cells (FAKΔmyeloid) were crossed with mice that develop spontaneous breast carcinomas due to expression of the MMTV-PyMT transgene. FAKΔmyeloid MMTV-PyMT mice showed significantly enhanced primary tumor outgrowth compared to wildtype (WT) littermate MMTV-PyMT animals. Tumors from both genotypes contained equivalent numbers of mature, F4/80-positive tumor-associated macrophages (TAMs), demonstrating that these cells were not dependent upon FAK to infiltrate/survive in the tumor. This was reinforced by adoptive transfer studies showing equal numbers of WT and FAKΔmyeloid bone marrow monocytes at the tumor site 30 minutes post-injection. Further analysis revealed that FAK expression was developmentally regulated, such that bone marrow cells and the immature Ly6C+cd11b+ cells present in circulation expressed nearly undetectable amounts of FAK protein. However, a substantial number of the cd11b+ cells within the tumor were Lyc6C-negative and had gained expression of FAK. Interestingly, the Ly6C-negative cells were shown to be more migratory than the Lyc6C+ monocytes, and this increased migration was dependent upon FAK expression. Based on these data, we propose that monocytes mature and upregulate FAK once they have successfully extravasated out of the tumor vasculature. This, in turn, allows increased movement of these cells within the tumor microenvironment, which may help to control tumor size/outgrowth through more effective clearance of necrotic cells and/or more global distribution of factors that could ultimately mediate an anti-tumor effect. Experiments are currently underway to test these possibilities. Citation Format: Ryan Llewellyn, Michael F. Gutknecht, Amy H. Bouton. Expression of Focal Adhesion Kinase (FAK) in myeloid lineage cells increases with maturation and regulates primary tumor growth in MMTV-PyVmT murine model of breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2879. doi:10.1158/1538-7445.AM2013-2879