Article

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.

Creador

• Schwartz, E. B.
• Ratner, N.
• Largaespada, D. A.
• Cancelas, Jose A.
• Stemmer-Rachamimov, A. O.

Licencia

• All rights reserved

Presentador

Jose Cancelas

Colegio

• Medicine

Departamento

• Hoxworth Blood Center

Fecha de creacion

• 2014-11

Editor

• Neuro-Oncology

Título de la revista

• 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.

Nota

• This work was part of a pilot "mediated-deposit model" where library staff found potential works, later submitted for faculty review

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