Pm-18 * Egfr-stat3 Activates -catenin Signaling to Drive Neurofibroma Initiation in Nf1, and Plays a Role in Tumor Maintenance
Year: 2014
Type: conference-abstract
Abstract: To identify genes and signaling pathways that drive peripheral nerve tumor initiation and growth beyond the Ras-MAPK pathway we used unbiased insertional mutagenesis screening. We identified Stat3 as a potential driver of Neurofibromatosis type 1 neurofibroma. Targeted genetic deletion of Stat3 in Schwann cell precursors (SCPs) and Schwann cells (SCs) largely prevented neurofibroma formation, and self-renewal of tumor initiating cells. Genetic gain- and loss-of-function identified EGFR as the major upstream regulator of P-Stat3 in mouse and human neurofibroma SCP and in neurofibroma initiation; IL-6 reinforced EGFR/Jak/Stat signaling. Preclinical tests of a Jak2/Stat3 inhibitor reduced established neurofibroma growth, supporting an additional role for Stat3 in benign nerve tumor maintenance. Unexpectedly, downstream of Stat3, we identified β-catenin, and β-catenin expression rescued phenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and β-catenin were strongly correlated in NF1 human plexiform neurofibromas. The data support testing of JAK/STAT inhibition and Wnt/ β-catenin pathway inhibition in neurofibroma therapeutic trials. Supported by: NIH R01 NS28840 to N.R. and NIH P50 NS057531 to N.R. and D.L.), a DAMD New Investigator Award (W81XWH-11-1-0259) and an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (to J.W.). The American Cancer Society (IRG-67-003-44) supported J.R.F.
Source: Neuro-Oncology
Authors: N. Ratner, V. Keng, D. M. Patmore, J. K. Kendall, E. Jousma, K. Choi, D. Fan, E. B. Schwartz, J. R. Fuchs, Y. Zou, M.-O. Kim, E. Dombi, D. E. Levy, J. A. Cancelas, A. Stemmer-Rachamimov, R. J. Spinner, D. A. Largaespada
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2324650343