Injury Signals Cooperate with Nf1 Loss to Relieve the Tumor-Suppressive Environment of Adult Peripheral Nerve

•Adult myelinating Schwann cells can be the cell of origin for neurofibromas•The nerve is tumor suppressive, given that Nf1−/− SCs remyelinate normally after injury•At the site of injury, Nf1−/− adult myelinating Schwann cells form tumors•Tumor cells are mostly S100− and some resemble the “perineurial-like” cells of tumors

SummarySchwann cells are highly plastic cells that dedifferentiate to a progenitor-like state following injury. However, deregulation of this plasticity, may be involved in the formation of neurofibromas, mixed-cell tumors of Schwann cell (SC) origin that arise upon loss of NF1. Here, we show that adult myelinating SCs (mSCs) are refractory to Nf1 loss. However, in the context of injury, Nf1-deficient cells display opposing behaviors along the wounded nerve; distal to the injury, Nf1−/− mSCs redifferentiate normally, whereas at the wound site Nf1−/− mSCs give rise to neurofibromas in both Nf1+/+ and Nf1+/− backgrounds. Tracing experiments showed that distinct cell types within the tumor derive from Nf1-deficient SCs. This model of neurofibroma formation demonstrates that neurofibromas can originate from adult SCs and that the nerve environment can switch from tumor suppressive to tumor promoting at a site of injury. These findings have implications for both the characterization and treatment of neurofibromas.

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