Targeting CXCL10 Chemokine Signaling in Breast Cancer Metastasis

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Project Summary/Abstract Cxcl10 is a chemokine that mediates leukocyte migration during normal immune response. In cancers, Cxcl10 has been considered as a good prognostic marker correlated with tumor immune infiltrates and therapy response, consistent with its normal function in cytotoxic immune response. As such, Cxcl10 has been utilized as an indicator of robust immune response to therapy in clinical trials and Cxcl10-based cancer therapy has been proposed. Paradoxically, Cxcl10 is associated with metastasis and poor patient survival in several cancers including breast cancer, suggesting that Cxcl10 may have a function of promoting cancer progression. The molecular context of this Cxcl10 oncogenic role is not well understood. This research team has identified CXCL10 as one of the inflammatory genes repressed by the ING4 tumor suppressor, which suggested a potential inverse functional relationship. Preliminary studies from the PI’s laboratory analyzed breast tumor gene expression datasets including METABRIC and found that CXCL10-high/ING4-low expression was significantly associated with reduced disease-free survival in patients. These data suggested that Cxcl10 may exert an oncogenic effect in the context of ING4 deficiencies. Corroborating this, Cxcl10 induced in vitro migration of ING4-deleted cells, but not of ING4-intact cells. The use of inhibitors demonstrated that Cxcl10- induced cell migration required Cxcr3 (the receptor for Cxcl10) and the Gbg subunits downstream of Cxcr3 G protein-coupled protein receptor (GPCR), but not Gai. These data indicated a novel mechanism of the Cxcl10/Cxcr3/Gbg axis that mediated migration of ING4-deleted cells and potentially metastasis. Based on these data, the hypothesis that Cxcl10/Cxcr3/Gbg signaling mediates metastasis of ING4-deficient cancer was generated. The overall goal of the study is to unravel the mechanism of Cxcl10 oncogenic signaling. To test the hypothesis for this Small Grants Program R03 proposal, the specific aims will focus on Gbg signaling as it may present novel therapeutic opportunities. The specific aims are: 1) to identify the specific Gbg subunits responsible for mediating Cxcl10-induced migration of ING4-deleted breast cancer cells in vitro and 2) to determine the role of Gbg in Cxcl10-induced metastasis of mammary tumors using mouse models. In mouse models, gallein (a Gbg inhibitor) and Gb/Gg gene deletion will be evaluated for inhibitory effects on Cxcl10- induced tumor metastasis. Impact: Up to 34% of breast cancers have been identified as ING4-deficient, which is correlated with lymph node positivity and poor patient survival. Thus, delineation of the Cxcl10/Cxcr3/Gbg/ING4 signaling mechanism may have a broad impact on breast cancer treatment. If the proposed hypothesis is proven correct, the cell and mouse models in the study can further be used to test novel therapeutic agents targeting the pathway.