Neuregulin-1 overexpression and Trp53 haploinsufficiency cooperatively promote de novo malignant peripheral nerve sheath tumor pathogenesis

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ID: 112041
2013
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Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are Schwann cell-derived malignancies that arise from plexiform neurofibromas in patients with mutation of the neurofibromin 1 (NF1) gene. We have shown that the growth factor neuregulin-1 (NRG1) also contributes to human neurofibroma and MPNST pathogenesis and that outbred C57BL/6J × SJL/J transgenic mice overexpressing NRG1 in Schwann cells (P0-GGFβ3 mice) recapitulate the process of neurofibroma-MPNST progression. However, it is unclear whether NRG1 acts predominantly within NF1-regulated signaling cascades or instead activates other essential cascades that cooperate with NF1 loss to promote tumorigenesis. We now report that tumorigenesis is suppressed in inbred P0-GGFβ3 mice on a C57BL/6J background. To determine whether NRG1 overexpression interacts with reduced Nf1 or Trp53 gene dosage to “unmask” tumorigenesis in these animals, we followed cohorts of inbred P0-GGFβ3;Nf1 +/−, P0-GGFβ3;Trp53 +/− and control (P0-GGFβ3, Nf1 +/− and Trp53 +/−) mice for 1 year. We found no reduction in survival or tumors in control and P0-GGFβ3;Nf1 +/− mice. In contrast, P0-GGFβ3;Trp53 +/− mice died on average at 226 days, with MPNSTs present in 95 % of these mice. MPNSTs in inbred P0-GGFβ3;Trp53 +/− mice arose de novo from micro-MPNSTs that uniformly develop intraganglionically. These micro-MPNSTs are of lower grade (WHO grade II–III) than the major MPNSTs (WHO grade III–IV); array comparative genomic hybridization showed that lower grade MPNSTs also had fewer genomic abnormalities. Thus, P0-GGFβ3;Trp53 +/− mice represent a novel model of low- to high-grade MPNST progression. We further conclude that NRG1 promotes peripheral nervous system neoplasia predominantly via its effects on the signaling cascades affected by Nf1 loss.
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brosius2013actaneuregulin-1 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Stephanie N. Brosius;Amy N. Turk;Stephanie J. Byer;Nicole M. Brossier;Latika Kohli;Amber Whitmire;Fady M. Mikhail;Kevin A. Roth;Steven L. Carroll;Stephanie N. Brosius;Amy N. Turk;Stephanie J. Byer;Nicole M. Brossier;Latika Kohli;Amber Whitmire;Fady M. Mikhail;Kevin A. Roth;Steven L. Carroll;
Journal acta neuropathologica
Year 2013
DOI
doi:10.1007/s00401-013-1209-3
URL
https://link.springer.com/article/10.1007/s00401-013-1209-3
Keywords
pathology neurosciences

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