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EGFR-Stat3 signalling in nerve glial cells modifies neurofibroma initiation

Oncogene volume 36, pages 1669–1677 (2017)Cite this article

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Abstract

Neurofibromatosis type 1 (NF1) is an inherited disease in which affected patients are predisposed to develop benign Schwann cell (SC) tumours called neurofibromas. In the mouse, loss of Nf1 in the SC lineage causes neurofibroma formation. The tyrosine kinase receptor EGFR is expressed in Schwann cell precursors (SCP), which have been implicated in plexiform neurofibroma initiation. To test if EGFR activity affects neurofibroma initiation, size, and/or number, we studied mice expressing human EGFR in SCs and SCP in the context of mice that form neurofibromas. Neurofibroma number increased in homozygous CNP-hEGFR mice versus heterozygous littermates, and neurofibroma number and size increased when CNP-hEGFR was crossed to Nf1fl/fl;DhhCre mice. Conversely, diminished EGFR signalling in Nf1fl/fl;DhhCre;Wa2/+ mice decreased neurofibroma number. In vivo transplantation verified the correlation between EGFR activity and neurofibroma formation. Mechanistically, expression of CNP-hEGFR increased SCP/neurofibroma-initiating cell self-renewal, a surrogate for tumour initiation, and activated P-Stat3. Further, Il-6 reinforced Jak2/Stat3 activation in SCPs and SCs. These gain- and loss-of function assays show that levels of tyrosine kinase expression in SCPs modify neurofibroma initiation.

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Acknowledgements

We thank Dr Luis F Parada (Memorial Sloan Kettering, NY) for Nf1fl/fl mice and Dr Anat O Stemmer-Rachamimov (Massachusetts General Hospital) for assistance with mouse pathology. We thank Dr Adam Lane (CCHMC) for consultation on statistical analysis. This work was supported by a DAMD New Investigator Award (W81XWH-11-1-0259) (Jianqiang Wu) and NIH R01 NS28840 (Nancy Ratner).

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Author notes

  1. W Liu

    Present address: 2Current address: Department of Pediatric Surgery, Provincial Hospital affiliated to Shandong University, P.R. China.,

  2. J P Williams

    Present address: 3Current address: San Antonio Military Medical Center – Neurology, 3551 Roger Brooke Drive, JBSA Fort Sam Houston, Texas, 78234-6200, USA.,

Authors and Affiliations

  1. Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Research Foundation, Cincinnati Children’s Hospital, University of Cincinnati, Cincinnati, OH, USA

    J Wu, W Liu, J P Williams & N Ratner

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Correspondence to N Ratner.

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Wu, J., Liu, W., Williams, J. et al. EGFR-Stat3 signalling in nerve glial cells modifies neurofibroma initiation. Oncogene 36, 1669–1677 (2017). https://doi.org/10.1038/onc.2016.386

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