Abstract 3172: CCL9 induction in myeloid cells of the premetastatic niche enhances tumor cell survival and metastatic colonization

Abstract

Abstract Tumor cell survival in the hostile distant organ is a rate-limiting step in cancer metastasis. Bone marrow-derived myeloid cells can form a premetastatic niche and provide a tumor-promoting microenvironment. However, it is unclear whether these myeloid cells in the premetastatic site have any direct effect on tumor cell survival. Here we report that chemokine CCL9 was highly induced in Gr-1+CD11b+ immature myeloid cells and in premetastatic lung of mice bearing 4T1 mammary tumor and B16 melanoma. Knockdown of CCL9 in myeloid cells decreased tumor cell survival and metastasis. The expression level of CCL23, the human orthologue for CCL9, in peripheral blood mononuclear cells correlated with progression and survival of cancer patients. Our studies identify CCL9 as a key pro-survival factor for cancer cells in the premetastatic organ. Interestingly, the expression of CCL9 in myeloid cells is regulated by TGF-β signaling as overexpression of CCL9 in myeloid cells lacking TGF-β signaling rescued the tumor metastasis defect observed in mice with myeloid-specific deletion of TGF-β signaling. These data together with our previous report of a fundamental role of myeloid TGF-β signaling in host compromised immune surveillance (Cancer Discovery 2013); demonstrate that myeloid-specific TGF-β signaling constitutes an essential component of the metastasis-promoting puzzle of TGF-β. This finding is different from TGF-β signaling in fibroblasts and a variety of epithelial cells, as well as T cells in which the TGF-β signaling functions as a tumor suppressor. This new understanding of TGF-β at the interface of tumor and host may provide insight into how TGF-β switches from a tumor suppressor to a tumor promoter, a long-standing challenge in cancer biology field. Our study demonstrates that CCL9 could serve as a good candidate for anti-metastasis treatment by targeting the rate-limiting step of cancer cell survival. Additionally, targeting CCL9 may avoid the adverse effects of TGF-β-targeted therapy. Citation Format: Hannah HY Yan, Yanli Pang, Kent Hunter, Chand Khanna, Li Yang. CCL9 induction in myeloid cells of the premetastatic niche enhances tumor cell survival and metastatic colonization. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3172. doi:10.1158/1538-7445.AM2015-3172