Abstract 1404: An EGFR-Stat3-IL6 pathway contributes to NF1 tumor initiation and maintenance

Abstract

Abstract Neurofibromas are incurable peripheral nerve tumors characteristic of Neurofibromatosis type 1. Development of effective neurofibroma therapies has been hindered by limited understanding of mechanisms underlying neurofibroma formation and growth. We used unbiased insertional mutagenesis screening to identify genes and signaling pathways that drive neurofibroma initiation and growth, and identified Stat3. Immunohistochemistry confirmed phosphorylated STAT3(P-Y705) in all human and mouse neurofibromas. Targeted genetic deletion of Stat3 in Schwann cell precursors (SCPs) and Schwann cells (SCs) significantly delayed neurofibroma formation, and in vitro analysis identified a role for Stat3 in SCP self-renewal and tumor initiation after xenografting. In vivo gain- and loss-of-function studies identified EGFR as the major upstream regulator of SCP P-Stat3. Downstream of P-Stat3, EGFR+ SCPs secreted IL-6, which activated SCPs and mature neurofibroma Schwann cells. Therefore, Stat3 plays a critical role in early SC lineage cells, promoting neurofibroma initiation. Jak/Stat might also play a role in neurofibroma maintenance, as a pharmacological Jak2/Stat3 inhibitor reduced Schwann cell and neurofibroma growth. The data support Jak/Stat as a novel neurofibroma driver pathway and JAK/STAT inhibition as a potential neurofibroma therapeutic strategy. Citation Format: Jianqiang Wu, Nancy Ratner. An EGFR-Stat3-IL6 pathway contributes to NF1 tumor initiation and maintenance. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1404. doi:10.1158/1538-7445.AM2014-1404