{"response":{"docs":[{"system_create_dtsi":"2017-10-27T02:31:35Z","system_modified_dtsi":"2018-08-01T18:36:52Z","has_model_ssim":["Article"],"id":"bc386t154","accessControl_ssim":["6e878354-fc4f-4bd4-a562-4360c50abe48"],"hasRelatedMediaFragment_ssim":["bc386t16d"],"hasRelatedImage_ssim":["bc386t16d"],"depositor_ssim":["cancelje@ucmail.uc.edu"],"depositor_tesim":["cancelje@ucmail.uc.edu"],"title_tesim":["PM-18 EGFR-STAT3 Activates B-Catenin Signaling to Drive Neurofibroma Initiation in Nf1, and Plays a Role in Tumor Maintenance"],"date_uploaded_dtsi":"2017-02-08T00:00:00Z","date_modified_dtsi":"2017-04-10T00:00:00Z","isPartOf_ssim":["admin_set/default"],"proxy_depositor_ssim":["peckjd@mail.uc.edu"],"journal_title_tesim":["PM-18. EGFR-STAT3 ACTIVATES b-CATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A ROLE IN TUMOR MAINTENANCE Nancy Ratner1, Vincent Keng2, Deanna M. Patmore1, Jed K. Kendall1, Edwin Jousma1, Kwangmin Choi1, Danhua Fan2, Eric B. Schwartz2, James R. Fuchs2, Yuanshu Zou2, Mi-Ok Kim1, Eva Dombi5, David E. Levy6, Jose A. Cancelas1, Anat Stemmer-Rachamimov4, Robert J. Spinner3, and David A. Largaespada2; 1 Cincinnati Children’s, Cincinnati, OH, USA; 2 University of Minnesota, Minneapolis, MN, USA; 3 Mayo Clinic, Rochester, MN, USA; 4 Massachusetts General Hospital, Boston, MA, USA; 5 National Cancer Institute Pediatric Branch, Bethesda, MD, USA; 6 New York University School of Medicine, New York, NY, USA To identify genes and signaling pathways that drive peripheral nerve tumor initiationand growth beyond the Ras-MAPK pathwaywe 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 b-catenin, and b-catenin expression rescued phenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and b-catenin were strongly correlated in NF1 human plexiform neurofibromas. The data support testing of JAK/STAT inhibition and Wnt/ b-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."],"college_tesim":["Medicine"],"department_tesim":["Hoxworth Blood Center"],"note_tesim":["This work was part of a pilot \"mediated-deposit model\" where library staff found potential works, later submitted for faculty review"],"creator_tesim":["Schwartz, E. B.","Ratner, N.","Largaespada, D. A.","Cancelas, Jose A.","Stemmer-Rachamimov, A. O."],"publisher_tesim":["Neuro-Oncology"],"description_tesim":["PM-18. EGFR-STAT3 ACTIVATES b-CATENIN SIGNALING TO\nDRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A\nROLE IN TUMOR MAINTENANCE\nNancy Ratner1, Vincent Keng2, Deanna M. Patmore1, Jed K. Kendall1,\nEdwin Jousma1, Kwangmin Choi1, Danhua Fan2, Eric B. Schwartz2, James\nR. Fuchs2, Yuanshu Zou2, Mi-Ok Kim1, Eva Dombi5, David E. Levy6, Jose\nA. Cancelas1, Anat Stemmer-Rachamimov4, Robert J. Spinner3, and David\nA. Largaespada2;\n1\nCincinnati Children’s, Cincinnati, OH, USA; 2\nUniversity of\nMinnesota, Minneapolis, MN, USA; 3\nMayo Clinic, Rochester, MN, USA; 4\nMassachusetts General Hospital, Boston, MA, USA; 5\nNational Cancer\nInstitute Pediatric Branch, Bethesda, MD, USA; 6\nNew York University School\nof Medicine, New York, NY, USA\nTo identify genes and signaling pathways that drive peripheral nerve tumor\ninitiationand growth beyond the Ras-MAPK pathwaywe used unbiased insertional\nmutagenesis screening. We identified Stat3 as a potential driver of\nNeurofibromatosis type 1 neurofibroma. Targeted genetic deletion of Stat3\nin Schwann cell precursors (SCPs) and Schwann cells (SCs) largely prevented\nneurofibroma formation, and self-renewal of tumor initiating cells. Genetic\ngain- and loss-of-function identified EGFR as the major upstream regulator\nof P-Stat3 in mouse and human neurofibroma SCP and in neurofibroma initiation;\nIL-6 reinforced EGFR/Jak/Stat signaling. Preclinical tests of a Jak2/\nStat3 inhibitor reduced established neurofibroma growth, supporting an additional\nrole for Stat3 in benign nerve tumor maintenance. Unexpectedly, downstream\nof Stat3, we identified b-catenin, and b-catenin expression rescued\nphenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and\nb-catenin were strongly correlated in NF1 human plexiform neurofibromas.\nThe data support testing of JAK/STAT inhibition and Wnt/ b-catenin\npathway inhibition in neurofibroma therapeutic trials. Supported by: NIH\nR01 NS28840 to N.R. and NIH P50 NS057531 to N.R. and D.L.), a\nDAMD New Investigator Award (W81XWH-11-1-0259) and an Ohio State\nUniversity Comprehensive Cancer Center Pelotonia Idea Grant (to J.W.).\nThe American Cancer Society (IRG-67-003-44) supported J.R.F."],"license_tesim":["http://rightsstatements.org/vocab/InC/1.0/"],"date_created_tesim":["2014-11"],"source_tesim":["PM-18. EGFR-STAT3 ACTIVATES b-CATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1, AND PLAYS A ROLE IN TUMOR MAINTENANCE Nancy Ratner1, Vincent Keng2, Deanna M. Patmore1, Jed K. Kendall1, Edwin Jousma1, Kwangmin Choi1, Danhua Fan2, Eric B. Schwartz2, James R. Fuchs2, Yuanshu Zou2, Mi-Ok Kim1, Eva Dombi5, David E. Levy6, Jose A. Cancelas1, Anat Stemmer-Rachamimov4, Robert J. Spinner3, and David A. Largaespada2; 1 Cincinnati Children’s, Cincinnati, OH, USA; 2 University of Minnesota, Minneapolis, MN, USA; 3 Mayo Clinic, Rochester, MN, USA; 4 Massachusetts General Hospital, Boston, MA, USA; 5 National Cancer Institute Pediatric Branch, Bethesda, MD, USA; 6 New York University School of Medicine, New York, NY, USA To identify genes and signaling pathways that drive peripheral nerve tumor initiationand growth beyond the Ras-MAPK pathwaywe 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 b-catenin, and b-catenin expression rescued phenotypic effects of Stat3 loss in SCPs. Phosphorylated STAT3 (Y705) and b-catenin were strongly correlated in NF1 human plexiform neurofibromas. The data support testing of JAK/STAT inhibition and Wnt/ b-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."],"thumbnail_path_ss":"/downloads/bc386t16d?file=thumbnail","suppressed_bsi":false,"actionable_workflow_roles_ssim":["admin_set/default-default-depositing"],"workflow_state_name_ssim":["deposited"],"member_ids_ssim":["bc386t16d"],"file_set_ids_ssim":["bc386t16d"],"visibility_ssi":"open","admin_set_tesim":["Default Admin Set"],"sort_title_ssi":"PM18 EGFRSTAT3 ACTIVATES BCATENIN SIGNALING TO DRIVE NEUROFIBROMA INITIATION IN NF1 AND PLAYS A ROLE IN TUMOR MAINTENANCE","human_readable_type_tesim":["Article"],"read_access_group_ssim":["public"],"edit_access_person_ssim":["cancelje@ucmail.uc.edu"],"nesting_collection__pathnames_ssim":["bc386t154"],"nesting_collection__deepest_nested_depth_isi":1,"_version_":1697125337642565632,"timestamp":"2021-04-15T16:40:46.232Z","score":0.00049999997}],"facets":[{"name":"human_readable_type_sim","items":[{"value":"Article","hits":1,"label":"Article"}],"label":"Human Readable Type Sim"},{"name":"creator_sim","items":[{"value":"Cancelas, Jose A.","hits":1,"label":"Cancelas, Jose A."},{"value":"Largaespada, D. 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