Abstract IA24: The role of CCL18 signaling in breast tumor associated macrophages promoting cancer progression

Abstract

Abstract Tumor-associated macrophages (TAMs) play critical roles in cancer progression. We focus on dissecting their underlying molecular mechanisms by applying human sample-based approaches, which include humanized mice, clinical samples and online clinical databases. Our data showed that CCL18, one of the most abundantly produced cytokines from human breast TAMs, is closely associated with advanced histopathological grading, triple negative breast cancer subtype, lymphovascular invasion, distant metastasis and poor prognosis of breast cancer patients. Mechanistic studies revealed that CCL18 induces epithelial-mesenchymal transition (EMT) and inflammatory cytokine secretion of tumor cells by activating NFkB pathway. Among the cytokines induced by CCL18, GM-CSF released from tumor cells undergone EMT in turn enhances the CCL18 production from TAMs and forms a positive feedback loop, which is essential to breast cancer metastasis, especially in the triple negative subtype. In addition, our recent study demonstrated that CCL18 could also mediate the activation and functions of other stromal cells in tumor microenvironment, leading to angiogenesis, recruitment of naïve T cells and activation of a special subset of chemoresistance-inducing fibroblasts. Previously, the receptor of CCL18 remained unknown. By using immunoprecipitation and mass spectra of the membrane extracts, cell-free isotope binding assays, [Ca2+]I mobilization and cAMP assays, we identified PITPNM3 as a functional receptor for CCL18. RNAi silencing of PITPNM3 in either cancer cells or stromal cells significantly inhibited the tumor progression in vivo. In conclusion, we define CCL18 from TAMs as the axis of a novel inflammatory signaling network in tumor microenvironment and imply the potential clinical application by targeting its receptor. Citation Format: Erwei Song. The role of CCL18 signaling in breast tumor associated macrophages promoting cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr IA24.