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

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 x 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+/− andTrp53+/−) 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.

Clinical genomic profiling identifies TYK2 mutation and overexpression in patients with neurofibromatosis type 1‐associated malignant peripheral nerve sheath tumors

“…On average, there were 67 mutations per tumor categorized as variants in: 1) genes associated with MPNST; 2) genes previously reported to be mutated in other cancers; or 3) mutations for which the clinical significance is currently unknown (Table ). Mutations were identified in 4 genes previously implicated in MPNST pathogenesis in both human studies and genetically engineered mouse models ( NF1, TP53, EGFR , and PDGFR‐α [ PDGFRA ]) . Variants also were identified in other genes potentially involved in MPNST pathogenesis ( GNAQ, SLCO1B1, LAMA2, SLC34A2, PTCH1, RB1, KDR, CYP2A6, MYC, FLT4 , and PSMD2 ) .…”

Polycomb repression regulates Schwann cell proliferation and axon regeneration after nerve injury

“…Previous studies have identified gene expression changes in MPNST’s with loss of PRC2 function (Lee et al 2014), and we found some of the same changes in our Eed cKO mice. More specifically, Eed cKO led to an upregulation of Nrg1 , which is also observed in neoplastic Schwann cells within human neurofibromas and MPNST’s (Stonecypher et al 2005), and aberrant NRG1 signaling contributes to the pathogenesis of neurofibromas and MPNST’s in mouse models (Brosius et al 2014; Gomez-Sanchez et al 2013; Huijbregts et al 2003; Kazmi et al 2013). In addition, SEMA4F-deficiency was also identified in models of Neurofibromatosis type 1 and human neurofibromas, and appears to be a mechanism of loss of Schwann cell-axonal interaction, which contributes to tumorigenesis (Parrinello et al 2008).…”

The Challenge of Cancer Genomics in Rare Nervous System Neoplasms

“…To determine whether NRG1 interacts with Nf1 or Trp53 loss, cohorts of inbred P 0 -GGFb3;Nf1 þ/À and P 0 -GGFb3;Trp53 þ/À mice were established and examined for evidence of tumor formation. 97 Although no tumors were seen in P 0 -GGFb3;Nf1 þ/À mice, virtually all of the P 0 -GGFb3;Trp53 þ/À mice developed MPNSTs. The MPNSTs in P 0 -GGFb3;Trp53 þ/À mice, like those in cis-linked Nf1 þ/À ; Trp53 þ/À mice, arose de novo, demonstrating that NRG1 overexpression could substitute for Nf1 loss and thus must promote tumorigenesis through the same signaling cascade affected by Nf1 loss.…”

“…transcriptome sequencing experiments have recently been presented at national meetings, only aCGH results are published, 96,97,100 and so I focus on those experiments here.…”

“…97,100 Examination of a series of P 0 -GGFb3;Trp53 þ/À MPNSTs that included World Health Organization grade II, III, and IV neoplasms showed that grade II tumors had fewer unbalanced copy number variations than grade IV lesions. Surprisingly, however, the number of copy number variations in grade III MPNSTs were not intermediate between grade II and IV neoplasms; instead, approximately one-half of the grade III MPNSTs had gains and losses that occurred with a frequency analogous to the grade IV tumors, with the remainder resembling the grade II MPNSTs.…”