Abstract 5041: The type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

Growth factors and their receptors coordinate neuronal differentiation during development, yet their roles in the pediatric tumor neuroblastoma remain unclear. Here we report that expression of type III TGF-beta receptor (TβRIII) mRNA and protein decreases with advancing stage of neuroblastoma and positively correlates with prognosis. TβRIII expression is epigenetically suppressed by MYCN oncogene amplification and TβRIII expression can be used as a prognostic marker in neuroblastoma patients with MYCN amplification. TβRIII expression in neuroblastoma cells promotes neuronal differentiation and enhances the differentiating effects of FGF2 treatment. Mechanistically, glycosaminoglycan modifications on TβRIII bind FGF2 and FGFR1 to promote neuronal differentiation via Erk MAPK and the transcription factor ID1. TβRIII-mediated differentiation suppresses tumor cell proliferation in vitro and in vivo. These studies characterize a novel co-receptor function for TβRIII in FGF2-mediated neuronal differentiation of neuroblastoma cells, while identifying potential therapeutic targets and clinical biomarkers for advanced-stage disease. More generally, our results suggest that the targeting of growth factor receptors and downstream signaling pathways may prove useful in promoting neuronal differentiation to suppress neuroblastoma tumor growth. Citation Format: Erik H. Knelson, Angela L. Gaviglio, Alok K. Tewari, Michael B. Armstrong, Andrew B. Nixon, Mark D. Starr, Karthikeyan Mythreye, Gerard C. Blobe. The type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma. [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 5041. doi:10.1158/1538-7445.AM2013-5041