Tumor-stromal interactions as targets of tumor metastasis suppressors

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DESCRIPTION (provided by applicant): Women with triple-negative breast cancer (TNBC) have the shortest survival and highest relapse rates; however, there are no known targeted therapies. Metastasis, the cause of most cancer-related deaths, is dependent upon specific molecular interactions between tumor cells and their microenvironment. We recently conducted a study to characterize these tumor-stromal interactions in a TNBC xenograft model. To identify drivers of metastasis, we compared gene expression in an invasive tumor, and a genetically matched noninvasive tumor that stably expressed the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP). Our studies revealed a striking loss of macrophage infiltration in noninvasive (RKIP+) tumors when compared to invasive tumors. Preliminary results suggest that RKIP inhibits expression of the macrophage chemokine, CCL5, in tumor cells and its receptor, CCR5, in the stroma. CCL5 overexpression in noninvasive (RKIP+) tumors partially rescued macrophage infiltration suggesting that CCL5 is sufficient to initiate metastasis. The CCL5-CCR5 axis has been implicated in BLBC metastasis, but its mechanisms of action and the role of macrophages are not known. We hypothesize that the chemokine CCL5 mediates interaction between TNBC cells and tumor-associated macrophages to drive invasion and metastasis AND that blocking CCL5 activity combined with targeted EGFR therapy in humanized mice will lead to reduced tumor and metastatic burden. We propose to elucidate the nature and role of these interactions. Specifically, we will: 1) Characterize CCL5-mediated crosstalk between TNBCs and TAMs; 2) Investigate the role of TAMs and Ccl5 in a TNBC mouse model; and 3) Investigate the mechanism by which RKIP regulates CCL5 expression and its potential therapeutic application. Our studies could both inform clinicians about risk factors leading to triple-negative breast cancer as well as lead to potential therapeutic targets.