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

J Wu; D M Patmore; E Jousma; D W Eaves; K Breving; A V Patel; E B Schwartz; J R Fuchs; T P Cripe; A O Stemmer-Rachamimov; N Ratner

doi:10.1038/onc.2012.579

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

Oncogene. 2014 Jan 9;33(2):173-80. doi: 10.1038/onc.2012.579. Epub 2013 Jan 14.

Authors

J Wu¹, D M Patmore¹, E Jousma¹, D W Eaves¹, K Breving¹, A V Patel¹, E B Schwartz², J R Fuchs², T P Cripe¹, A O Stemmer-Rachamimov³, N Ratner¹

Affiliations

¹ Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
² Ohio State University, College of Pharmacy, Columbus, OH, USA.
³ Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cells, Cultured
Curcumin / analogs & derivatives
Curcumin / pharmacology
ErbB Receptors / physiology*
Genes, Neurofibromatosis 1
Humans
Janus Kinase 2 / physiology
Mice
Mice, Inbred C57BL
Nerve Sheath Neoplasms / etiology*
STAT3 Transcription Factor / antagonists & inhibitors
STAT3 Transcription Factor / physiology*
Sarcoma / etiology
Signal Transduction / physiology*

Substances

FLLL 32
STAT3 Transcription Factor
ErbB Receptors
Janus Kinase 2
Curcumin

Abstract

Publication types

MeSH terms

Substances

Grants and funding