Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation

• Published in: Cell reports (Cambridge) Vol. 14; no. 8; pp. 1979 - 1990
• Main Authors: Wu, Jianqiang, Keng, Vincent W., Patmore, Deanna M., Kendall, Jed J., Patel, Ami V., Jousma, Edwin, Jessen, Walter J., Choi, Kwangmin, Tschida, Barbara R., Silverstein, Kevin A.T., Fan, Danhua, Schwartz, Eric B., Fuchs, James R., Zou, Yuanshu, Kim, Mi-Ok, Dombi, Eva, Levy, David E., Huang, Gang, Cancelas, Jose A., Stemmer-Rachamimov, Anat O., Spinner, Robert J., Largaespada, David A., Ratner, Nancy
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2016; Elsevier
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Carcinogenesis - genetics; Carcinogenesis - metabolism; Carcinogenesis - pathology; Disease Models, Animal; DNA Helicases - genetics; DNA Helicases - metabolism; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Histones - genetics; Histones - metabolism; Humans; Mice; Mice, Nude; Mutagenesis, Insertional; N-Terminal Acetyltransferase A - antagonists & inhibitors; N-Terminal Acetyltransferase A - genetics; N-Terminal Acetyltransferase A - metabolism; Neoplasm Transplantation; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurofibromatosis 1 - genetics; Neurofibromatosis 1 - metabolism; Neurofibromatosis 1 - pathology; Neurofibromin 1 - genetics; Neurofibromin 1 - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Peripheral Nervous System Neoplasms - genetics; Peripheral Nervous System Neoplasms - metabolism; Peripheral Nervous System Neoplasms - pathology; Phosphorylation; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Schwann Cells - metabolism; Schwann Cells - pathology; Signal Transduction; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.01.074

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. [Display omitted] •Insertional mutagenesis identifies STAT3 as a driver of benign neurofibromas•Stat3 activates β-catenin to initiate neurofibroma formation•Stat3 represses Gsk3β and Arid1b to increase β-catenin•Neurofibroma-initiating cells require Stat3 and β-catenin for tumorigenesis Wu et al. map an Nf1-Stat3-Arid1b/β-catenin pathway that initiates Neurofibromatosis type 1 (Nf1) neurofibromas, using unbiased insertional mutagenesis screening. Stat3 transcriptionally represses Gsk3β and Arid1b, thereby activating β-catenin in Schwann cell precursors and resulting in neurofibroma initiation and maintenance. Stat3-mediated modification plays a role in early tumorigenesis.