Abstract A23: ALK activity in macrophages drives metastasis in murine models of breast cancer

Abstract

Abstract VEGF-induced angiogenesis and macrophages contribute directly to metastasis, the leading cause of breast cancer related mortality. VEGF is a major driver of angiogenesis, yet its targeted inhibition is often ineffective at controlling metastases. In contrast, pathways that contribute to a pro-metastatic macrophage phenotype are unclear and pharmacological strategies to inhibit pro-metastatic activity are lacking. In this study, we illustrate that anti-VEGF therapy modulates PTN expression in multiple mouse models of breast cancer. Once expressed, PTN induces the expression of VEGFR2 on macrophages and promotes an anti-inflammatory, pro-metastatic macrophage phenotype. This phenomenon is dependent on ALK signaling, as inhibition with the small molecule receptor tyrosine kinase inhibitor crizotinib (Xalkori, Pfizer), which targets ALK, or ALK siRNA is sufficient to reverse PTN-induced VEGFR2 and anti-inflammatory macrophage marker expression. Importantly, phosphorylated ALK and VEGFR2 positive macrophages were detected in tumor but not normal breast tissue from patients. Furthermore, inhibition of ALK signaling in macrophages blunted metastasis but had no effect on primary MMTV-PyMT tumors; while blockade of VEGF slowed primary tumor growth without effect on metastatic burden. Combined inhibition of ALK and VEGF activity showed potent anti-tumor and anti-metastatic activity in animals with disseminated disease. Collectively, our data document novel markers of pro-metastatic macrophages and reveal how macrophage phenotype can be manipulated to suppress breast cancer progression. Citation Format: Kristi D. Lynn, Rolf A. Brekken. ALK activity in macrophages drives metastasis in murine models of breast cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A23. doi:10.1158/1538-7445.CHTME14-A23