Abstract 2134: IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis

Osteosarcoma (OS) kills patients through aggressive metastatic spread, primarily to lung tissues. Our lab has sought to understand the tumor-host interactions that facilitate growth of OS cells specifically within the lung. We previously identified two intercellular signaling molecules, IL6 and CXCL8, which exhibit enhanced expression when primary tumors become lung metastases. Here, we show that epigenetic changes drive aberrant expression of ΔNp63, endowing OS cells with the capacity to colonize lung tissue. IL6 and CXCL8 serve as downstream mediators induced directly by ΔNp63 and necessary for survival and proliferation within the lung. Inhibition of IL6 and CXCL8 signaling has no direct effect on the proliferation of OS cells, but IL6 inhibition has a profound effect on their ability to form colonies in soft agar. In preclinical mouse models of OS, inhibitors of IL6 and CXCL8 signaling profoundly impair the ability of OS cells to colonize lung tissue, completely preventing metastasis in some models. Co-culture studies suggest that strong paracrine interactions with bronchial epithelial and smooth muscle cells, but not macrophages or lung fibroblasts, drive increased expression of IL6 and CXCL8. These data suggest a mechanism where aberrant ΔNp63 expression within developing OS tumors generates subsets of tumor cells endowed with increased IL6 and CXCL8 expression. This triggers feed-forward paracrine loops with bronchial epithelial and smooth muscle cells that facilitate growth and survival within the lung, leading to metastasis. Citation Format: Ryan D. Roberts, Hakan Cam, Laura Brandolini, John M. Hinckley, Amy C. Gross. IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2134.