Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that arise sporadically or in association with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. In individuals with NF1, MPNSTs are hypothesized to arise from Nf1-deficient Schwann cell precursor cells following the somatic acquisition of secondary cooperating genetic mutations (e.g., p53 loss). To model this sequential genetic cooperativity, we coupled somatic lentivirus-mediated p53 knockdown in the adult right sciatic nerve with embryonic Schwann cell precursor Nf1 gene inactivation in two different Nf1 conditional knockout mouse strains. Using this approach, ∼60% of mice with Periostin-Cre-mediated Nf1 gene inactivation (Periostin-Cre; Nf1flox/flox mice) developed tumors classified as low-grade MPNSTs following p53 knockdown (mean, 6 months). Similarly, ∼70% of Nf1+/− mice with GFAP-Cre-mediated Nf1 gene inactivation (GFAP-Cre; Nf1flox/null mice) developed low-grade MPNSTs following p53 knockdown (mean, 3 months). In addition, wild-type and Nf1+/− mice with GFAP-Cre-mediated Nf1 loss develop MPNSTs following somatic p53 knockout with different latencies, suggesting potential influences of Nf1+/− stromal cells in MPNST pathogenesis. Collectively, this new MPNST model system permits the analysis of somatically-acquired events as well as tumor microenvironment signals that potentially cooperate with Nf1 loss in the development and progression of this deadly malignancy.
Highlights
Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive subtype of soft-tissue sarcoma that develops in association with peripheral nerves or nerve roots
To generate a model in which temporal control of the transforming genetic alteration can be achieved in a single nerve location, we employed two genetically-engineered mouse (GEM) strains in which Cre-mediated Nf1 inactivation occurs in Schwann cell precursor cells during embryogenesis and p53 knockdown is somatically acquired at 6-8 weeks of age in cells within the right sciatic nerve
Leveraging whole exome sequencing methodologies, a recent study from our laboratory revealed a temporal sequence of genetic changes in a single patient with progression of an Neurofibromatosis type 1 (NF1)-associated plexiform neurofibroma to MPNST over a 14-year period
Summary
MPNSTs are an aggressive subtype of soft-tissue sarcoma that develops in association with peripheral nerves or nerve roots. To generate a model in which temporal control of the transforming genetic alteration can be achieved in a single nerve location, we employed two GEM strains in which Cre-mediated Nf1 inactivation occurs in Schwann cell precursor cells during embryogenesis and p53 knockdown is somatically acquired at 6-8 weeks of age in cells within the right sciatic nerve.
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