Abstract 3785: Elevated expression of Fn14 in non-small cell lung cancer correlates with c-MET and promotes tumor cell invasion and metastasis.

Abstract

Abstract Tumor invasiveness and therapeutic resistance strongly contribute to the low (<10%) five-year survival rate for advanced stage lung cancer; thus, identification of novel interventions targeting metastasis and therapeutic resistance is a necessity. Hepatocyte growth factor receptor (c-Met) and fibroblast growth factor-inducible 14 (Fn14) are two cell surface receptors known to be associated with lung cancer invasiveness and cell survival. Our lab recently demonstrated that Fn14 was over-expressed in non-small cell lung cancer (NSCLC), correlated with activated epidermal growth factor receptor, and that expression of Fn14 modulated NSCLC cell invasiveness and metastasis. We hypothesize that elevated Fn14 expression can be maintained by c-Met activation, and that blockade of Fn14 can suppress NSCLC invasiveness driven by c-Met. Here we demonstrate that Fn14 protein expression significantly correlated with c-Met expression in primary NSCLC patient tumors. Fn14 and c-Met were more highly expressed in metastatic tumors compared to patient-matched primary NSCLC tumors, suggesting a role in the metastatic phenotype. To further elucidate the relationship between Fn14 and c-Met in NSCLC invasiveness, we employed two cell lines derived from a primary tumor (H2073) and metastatic lymph node (H1993) of the same patient. H1993 cells (c-Met receptor amplification) expressed significantly elevated protein levels of Fn14 compared to H2073 (low c-Met), which were significantly diminished in H1993 cells upon c-Met inhibition through SU11274 treatment. Moreover, exposure of H2073 cells to HGF induced the protein expression of Fn14. The elevated expression of Fn14 through HGF stimulation (H2073) or c-Met receptor amplification (H1993) was attenuated by pretreatment of the cells with U0126, a potent MEK inhibitor, suggesting that c-Met-induced Fn14 expression may depend on MAPK signaling. To further elucidate the effect of Fn14 on global c-Met-induced expression, genome-wide expression analysis was employed to determine genes both over-expressed in H1993 compared to H2073 and subsequently suppressed in Fn14 depleted H1993 cells. RALGPS2, a gene over-expressed in lung tumors that induces of c-fos and OPRL1, a gene elevated in metastatic melanoma, were elevated in the metastatic cell line and subsequently suppressed with Fn14 depletion. In addition, shRNA-mediated depletion of Fn14 in H1993 cells attenuated cell migration and invasion by 45% and 40%, respectively. This work demonstrates that c-Met and Fn14 may play a critical role in NSCLC metastasis, and suggests that targeting Fn14 may impact c-Met-driven NSCLC invasiveness. Successful targeting of NSCLC invasiveness would have significant clinical impact on a disease that is deadly in its advanced stages. Citation Format: Timothy G. Whitsett, Shannon P. Fortin, Paul A. Kurywchak, Julianna Ross, Janine LoBello, Christopher B. Kingsley, Jeffrey W. Allen, Glen J. Weiss, Nhan L. Tran. Elevated expression of Fn14 in non-small cell lung cancer correlates with c-MET and promotes tumor cell invasion and metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3785. doi:10.1158/1538-7445.AM2013-3785