Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation
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 delet...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-03-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716300675 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Jianqiang Wu Vincent W. Keng Deanna M. Patmore Jed J. Kendall Ami V. Patel Edwin Jousma Walter J. Jessen Kwangmin Choi Barbara R. Tschida Kevin A.T. Silverstein Danhua Fan Eric B. Schwartz James R. Fuchs Yuanshu Zou Mi-Ok Kim Eva Dombi David E. Levy Gang Huang Jose A. Cancelas Anat O. Stemmer-Rachamimov Robert J. Spinner David A. Largaespada Nancy Ratner |
| spellingShingle |
Jianqiang Wu Vincent W. Keng Deanna M. Patmore Jed J. Kendall Ami V. Patel Edwin Jousma Walter J. Jessen Kwangmin Choi Barbara R. Tschida Kevin A.T. Silverstein Danhua Fan Eric B. Schwartz James R. Fuchs Yuanshu Zou Mi-Ok Kim Eva Dombi David E. Levy Gang Huang Jose A. Cancelas Anat O. Stemmer-Rachamimov Robert J. Spinner David A. Largaespada Nancy Ratner Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation Cell Reports |
| author_facet |
Jianqiang Wu Vincent W. Keng Deanna M. Patmore Jed J. Kendall Ami V. Patel Edwin Jousma Walter J. Jessen Kwangmin Choi Barbara R. Tschida Kevin A.T. Silverstein Danhua Fan Eric B. Schwartz James R. Fuchs Yuanshu Zou Mi-Ok Kim Eva Dombi David E. Levy Gang Huang Jose A. Cancelas Anat O. Stemmer-Rachamimov Robert J. Spinner David A. Largaespada Nancy Ratner |
| author_sort |
Jianqiang Wu |
| title |
Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation |
| title_short |
Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation |
| title_full |
Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation |
| title_fullStr |
Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation |
| title_full_unstemmed |
Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma Initiation |
| title_sort |
insertional mutagenesis identifies a stat3/arid1b/β-catenin pathway driving neurofibroma initiation |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2016-03-01 |
| description |
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. |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124716300675 |
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doaj-b85859bc4dea43bd98344313076ad5bb2020-11-24T21:55:28ZengElsevierCell Reports2211-12472016-03-011481979199010.1016/j.celrep.2016.01.074Insertional Mutagenesis Identifies a STAT3/Arid1b/β-catenin Pathway Driving Neurofibroma InitiationJianqiang Wu0Vincent W. Keng1Deanna M. Patmore2Jed J. Kendall3Ami V. Patel4Edwin Jousma5Walter J. Jessen6Kwangmin Choi7Barbara R. Tschida8Kevin A.T. Silverstein9Danhua Fan10Eric B. Schwartz11James R. Fuchs12Yuanshu Zou13Mi-Ok Kim14Eva Dombi15David E. Levy16Gang Huang17Jose A. Cancelas18Anat O. Stemmer-Rachamimov19Robert J. Spinner20David A. Largaespada21Nancy Ratner22Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USAMasonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USAMasonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USABiostatistics and Informatics, University of Minnesota, Minneapolis, MN 55455, USABiostatistics and Informatics, University of Minnesota, Minneapolis, MN 55455, USAOhio State University, College of Pharmacy, Columbus, OH 43210, USAOhio State University, College of Pharmacy, Columbus, OH 43210, USADivision of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USADivision of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USAPediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USADepartment of Pathology and New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USADepartment of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USADepartment of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USAMasonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USADivision of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital University of Cincinnati, Cincinnati, OH 45229, USATo 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.http://www.sciencedirect.com/science/article/pii/S2211124716300675 |