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EGFR–STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors

Oncogene volume 33, pages 173–180 (2014)Cite this article

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Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) develop sporadically or in the context of neurofibromatosis type 1. Epidermal growth factor receptor (EGFR) overexpression has been implicated in MPNST formation, but its precise role and relevant signaling pathways remain unknown. We found that EGFR overexpression promotes mouse neurofibroma transformation to aggressive MPNST (GEM-PNST). Immunohistochemistry demonstrated phosphorylated STAT3 (Tyr705) in both human MPNST and mouse GEM-PNST. A specific JAK2/STAT3 inhibitor FLLL32 delayed MPNST formation in an MPNST xenograft nude mouse model. STAT3 knockdown by shRNA prevented MPNST formation in vivo. Finally, reducing EGFR activity strongly reduced pSTAT3 in vivo. Thus, an EGFR–STAT3 pathway is necessary for MPNST transformation and establishment of MPNST xenografts growth but not for tumor maintenance. Efficacy of the FLLL32 pharmacological inhibitor in delaying MPNST growth suggests that combination therapies targeting JAK/STAT3 might be useful therapeutics.

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Acknowledgements

We thank Dr Andre Bernards (Massachusetts General Hospital) and Drs Jiayuh Lin, Pui-Kai Li and Gregory B Lesinski (Ohio State University) for helpful discussions. This work was supported by the National Institutes of Health (R01 NS28840 and P50 NS057531 to NR), and Department of Defense New Investigator Award (NF100053) and an Ohio State University Comprehensive Cancer Center Pelotonia Idea Grant (to JW). The American Cancer Society (IRG-67-003-44) supported JRF.

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Authors and Affiliations

  1. Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    J Wu, D M Patmore, E Jousma, D W Eaves, K Breving, A V Patel, T P Cripe & N Ratner

  2. Ohio State University, College of Pharmacy, Columbus, OH, USA

    E B Schwartz & J R Fuchs

  3. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    A O Stemmer-Rachamimov

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Wu, J., Patmore, D., Jousma, E. et al. EGFR–STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene 33, 173–180 (2014). https://doi.org/10.1038/onc.2012.579

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