Abstract 2391: Microglia-stimulated glioblastoma cell invasion is dependent on the EGFR ligand amphiregulin

Abstract

Glioblastoma Multiforme (GBM) is one of the deadliest human cancers with a median survival rate of only one year following diagnosis. The highly infiltrative nature of GBM is one of the main reasons this cancer is so difficult to completely remove surgically. Therefore increasing our knowledge of the mechanism GBM cells use to invade normal brain is of critical importance in designing novel therapies. We recently showed that tumor associated microglia stimulate GBM cell invasion and this process is mediated by CSF-1R signaling. In this study, we seek to identify factors that are upregulated in microglia in a CSF-1R-dependent manner and ascertain whether they are involved in mediating invasion of GBM cells. We assayed cDNA and protein from microglia treated with conditioned media from the murine GBM cell line GL261, and discovered that the EGFR ligand amphiregulin (AREG) is strongly upregulated. This upregulation is blocked by addition of a pharmacological CSF-1R inhibitor. Using RNA interference, we show that microglia depleted of AREG can not promote invasion of GL261 cells into matrigel-coated invasion chambers as effectively. In addition, an AREG blocking antibody strongly attenuates the ability of THP1 macrophages to activate human GBM cell line U87 invasion. Furthermore, we have identified a signaling pathway which involves CSF-1R signaling through MAPK ERK to upregulate AREG expression in microglia and interfering with ERK using pharmacological inhibitors also prevents microglia-stimulated GL261 invasion. Interestingly, microglia that have been activated by GBM cells appear to require cell-cell contact in order to promote invasion. This data highlights AREG as a key factor in produced by tumor associated microglia in promoting glioblastoma invasion. Citation Format: Bhavika Desai, Uttama Rath, Jeffrey E. Segall, Salvatore J. Coniglio. Microglia-stimulated glioblastoma cell invasion is dependent on the EGFR ligand amphiregulin. [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 2391. doi:10.1158/1538-7445.AM2015-2391