| Title |
Neuregulin-1 overexpression and Trp53 haploinsufficiency cooperatively promote de novo malignant peripheral nerve sheath tumor pathogenesis
|
|---|---|
| Published in |
Acta Neuropathologica, November 2013
|
| DOI | 10.1007/s00401-013-1209-3 |
| Pubmed ID | |
| 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 |
| 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. |
X Demographics
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Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United States | 1 | 100% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Scientists | 1 | 100% |
Mendeley readers
The data shown below were compiled from readership statistics for 25 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 25 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Doctoral Student | 5 | 20% |
| Student > Ph. D. Student | 5 | 20% |
| Researcher | 4 | 16% |
| Student > Master | 4 | 16% |
| Professor | 3 | 12% |
| Other | 3 | 12% |
| Unknown | 1 | 4% |
| Readers by discipline | Count | As % |
|---|---|---|
| Medicine and Dentistry | 7 | 28% |
| Biochemistry, Genetics and Molecular Biology | 5 | 20% |
| Neuroscience | 4 | 16% |
| Agricultural and Biological Sciences | 4 | 16% |
| Veterinary Science and Veterinary Medicine | 1 | 4% |
| Other | 2 | 8% |
| Unknown | 2 | 8% |
Attention Score in Context
This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 16 November 2013.
All research outputs
#17,703,558
of 22,731,677 outputs
Outputs from Acta Neuropathologica
#2,167
of 2,363 outputs
Outputs of similar age
#150,749
of 211,390 outputs
Outputs of similar age from Acta Neuropathologica
#30
of 38 outputs
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