Poster abstracts

Poster number 73 submitted by Katie Thies

Determining the Role of CSF-1 Receptor Signaling in Tumor Associated Macrophages during the Progression of Breast Cancer Metastasis within the Brain

Katie A. Thies (Department of Molecular and Cellular Biochemistry, The Ohio State University), Haritha Mathsyaraja (Department of Molecular and Cellular Biochemistry, The Ohio State University), W. Hans Meisen (Department of Neurological Surgery, The Ohio State University), Balveen Kaur (Department of Neurological Surgery, The Ohio State University), Michael C. Ostrowski (Department of Molecular and Cellular Biochemistry, The Ohio State University)

Abstract:
Over the past several years, studies have highlighted a role for the tumor microenvironment in contributing to metastatic progression. While there is increasing evidence that tumor associated macrophages (TAMs) facilitate metastasis, the role of resident microglia in the context of brain metastasis remains unclear. The myeloid cell survival factor, CSF1, is produced by tumor cells and is known to promote macrophage recruitment to metastatic sites. We have shown that signaling through the CSF1 receptor activates a specific set of microRNA, including miR-21 and miR-29a, in metastatic lung TAMs which regulate certain pro-tumor processes. Interestingly, interleukin-34, a newly identified CSF1 receptor ligand, is highly expressed in the brain. However, the involvement of IL-34 during metastasis has been largely unexplored. Thus, we wish to investigate the role of IL-34 or CSF1-dependent microRNA in microglia and their effect on pro-tumor processes in the context of brain metastasis. We have employed an intracranial injection model using metastatic mammary tumor cells to experimentally induce metastases in syngeneic mice. So far, the brains of tumor-bearing and control mice have been characterized by immunofluorescent staining for blood vessels, macrophages, and markers of proliferation. After isolating a nearly pure population of microglia/macrophages from the brains of tumor-bearing mice, we found increased levels of miR-21, miR-29a and miR-223 when compared to PBS-injected controls. In vitro experiments using BV2 microglia cells show microRNA activation upon stimulation with IL-34, lending additional support to our hypothesis. In the future, we would like to develop an intracarotid artery injection model to better recapitulate brain metastasis. Still, our experimental brain metastasis model using immunocompetent mice has allowed us to address important questions pertaining to interactions amongst cells of the tumor microenvironment.

References:
1. Lin, E.Y., Nguyen, A.V., Russell, R.G. and Pollard, J.W. Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy. J. Exp. Med. 193, 727-740 (2001).
2. Nandi, S. et al. The CSF-1 Receptor Ligands IL-34 and CSF-1 Exhibit Distinct Developmental Brain Expression Patterns and Regulate Neural Progenitor Cell Maintenance and Maturation. Dev. Bio. 367, 100-113 (2012).
3. Wei, S. et al. Functional Overlap but Differential Expression of CSF-1 and IL-34 in their CSF-1 Receptor-Mediated Regulation of Myeloid Cells. J. Leukoc. Bio. 88(3), 495-505 (2010).
4. Wyckoff, J. et al. A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary Tumors. Cancer Res. 64, 7022-7029 (2004).

Keywords: Tumor Associated Macrophages, Breast Cancer, Metastasis