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

Cell Reports
Jianqiang WuNancy Ratner

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 Stat3(fl/fl);Nf1(fl/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.

References

Jul 11, 2002·Current Molecular Medicine·T E Battle, D A Frank
Jan 2, 2009·Pediatrics·Virginia C WilliamsBernard L Maria
Jun 23, 2009·Journal of the American Academy of Dermatology·Kevin P BoydAmy Theos
Jul 30, 2009·Nature Reviews. Molecular Cell Biology·Mohammad Ali Faghihi, Claes Wahlestedt
Nov 4, 2009·Trends in Biochemical Sciences·Dianqing Wu, Weijun Pan
May 1, 2012·Trends in Genetics : TIG·Marco MagistriClaes Wahlestedt
Dec 12, 2012·The Journal of Clinical Investigation·Walter J JessenNancy Ratner
Jun 1, 2013·Proceedings of the National Academy of Sciences of the United States of America·Michael Y TolstorukovCharles W M Roberts
Nov 13, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Armelle LuscanEric Pasmant
Feb 25, 2014·Nature Medicine·Katherine C HelmingCharles W M Roberts
Sep 5, 2015·American Journal of Human Genetics·Georgia VasileiouMichel V Hadjihannas

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Citations

Apr 19, 2018·Expert Opinion on Therapeutic Targets·James A Walker, Meena Upadhyaya
Oct 4, 2018·Environmental and Molecular Mutagenesis·Yi ZhaoZongbin Cui
Jan 11, 2019·Oncotarget·Zhuo XingY Eugene Yu
Nov 14, 2019·Journal of Drug Targeting·Bingqiao HuangWanggang Zhang
May 23, 2020·British Journal of Cancer·Jean-Philippe BrosseauLu Q Le
Feb 8, 2019·JCI Insight·Jonathan S FletcherNancy Ratner
Apr 10, 2019·Nature Biomedical Engineering·Bipasha Mukherjee-ClavinGabsang Lee
Apr 30, 2019·Science Advances·Ashley HallJianqiang Wu
Feb 14, 2020·International Journal of Molecular Sciences·Pauline J Beckmann, David A Largaespada
Sep 9, 2017·Future Science OA·Greta M BauerVadim Backman
Dec 14, 2018·Oncogene·Jonathan S FletcherNancy Ratner
Jul 10, 2020·Neuro-oncology Advances·Jonathan S FletcherNancy Ratner
Jul 9, 2020·Nature Reviews. Cancer·Julia WeberRoland Rad
Aug 9, 2020·Human Molecular Genetics·Ummi Ciptasari, Hans van Bokhoven
Oct 11, 2017·Cancer Research·Ophélia MaertensKaren Cichowski
Jun 27, 2021·Proceedings of the National Academy of Sciences of the United States of America·Prem Swaroop YadavYingzi Yang

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