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Title: | Insertional mutagenesis identifies a STAT3/Arid1b/β-catenin pathway driving neurofibroma initiation | Authors: | Wu, J Keng, VW Patmore, DM Kendall, JJ Patel, AV Jousma, E Jessen, WJ Choi, K Tschida, BR Silverstein, KAT Fan, D Schwartz, EB Fuchs, JR Zou, Y Kim, MO Dombi, E Levy, DE Huang, G Cancelas, JA Stemmer-Rachamimov, AO Spinner, RJ Largaespada, DA Ratner, N |
Issue Date: | 2016 | Source: | Cell reports, 2016, v. 14, no. 8, p. 1979-1990 | Abstract: | To identify genes and signaling pathways that initiate Neurofibromatosis type 1 (NF1) neurofibromas, we used unbiased insertional mutagenesis screening, mouse models, and molecular analyses. We mapped an Nf1-Stat3-Arid1b/β-catenin pathway that becomes active in the context of Nf1 loss. Genetic deletion of Stat3 in Schwann cell progenitors (SCPs) and Schwann cells (SCs) prevents neurofibroma formation, decreasing SCP self-renewal and β-catenin activity. β-catenin expression rescues effects of Stat3 loss in SCPs. Importantly, P-STAT3 and β-catenin expression correlate in human neurofibromas. Mechanistically, P-Stat3 represses Gsk3β and the SWI/SNF gene Arid1b to increase β-catenin. Knockdown of Arid1b or Gsk3β in Stat3fl/fl;Nf1fl/fl;DhhCre SCPs rescues neurofibroma formation after in vivo transplantation. Stat3 represses Arid1b through histone modification in a Brg1-dependent manner, indicating that epigenetic modification plays a role in early tumorigenesis. Our data map a neural tumorigenesis pathway and support testing JAK/STAT and Wnt/β-catenin pathway inhibitors in neurofibroma therapeutic trials. | Publisher: | Cell Press | Journal: | Cell reports | ISSN: | 2211-1247 | DOI: | 10.1016/j.celrep.2016.01.074 | Rights: | © 2016 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The following publication Wu, J., Keng, V. W., Patmore, D. M., Kendall, J. J., Patel, A. V., Jousma, E., ... & Fan, D. (2016). Insertional mutagenesis identifies a STAT3/Arid1b/β-catenin pathway driving neurofibroma initiation. Cell reports, 14(8), 1979-1990, is available at https://doi.org/10.1016/j.celrep.2016.01.074 |
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