Neuregulin-1 overexpression and Trp53 haploinsufficiency cooperatively promote de novo malignant peripheral nerve sheath tumor pathogenesis.
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.
Stephanie N
SN
Brosius
Amy N
AN
Turk
Stephanie J
SJ
Byer
Nicole M
NM
Brossier
Latika
L
Kohli
Amber
A
Whitmire
Fady M
FM
Mikhail
Kevin A
KA
Roth
Steven L
SL
Carroll
D000818:Animals; D003893:Desmin / Q000378:metabolism; D015870:Gene Expression; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism*; D009455:Neurofibroma / Q000235:genetics; D019574:Optic Nerve Neoplasms / Q000235:genetics* / Q000473:pathology*; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D003893:Desmin; D019394:Ki-67 Antigen; D018993:Myelin P0 Protein; D020890:Neuregulin-1; D064568:S100 Calcium Binding Protein beta Subunit; D016159:Tumor Suppressor Protein p53