Microenvironmental TGF-β is an early driver of NF1-associated tumor formation.

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome characterized by neurofibromas, Nf1-/- Schwann cell (SC)-derived tumors of peripheral nerves. We and others have shown that Nf1 loss in SCs is insufficient for neurofibroma formation but cooperates with an injury microenvironment to form tumors, but the mechanisms remain unknown. Here, we identify TGF-β as the microenvironmental injury signal that is essential for tumorigenesis. Analysis of the earliest stages of neurofibroma formation showed that tumor formation is associated with a population of Nf1-/- SCs that "escape" the regenerating nerve shortly after injury. Here, they reside in a distinct microenvironment conducive to tumorigenesis, where TGF-β disrupts SC/axonal interactions and SC re-differentiation. Pharmacological inhibition of TGF-β for a short therapeutic window during this early stage inhibited tumor formation, highlighting the potential to normalize Nf1-/- SCs and identifying TGF-β as a potential therapeutic target to both treat and prevent neurofibroma formation.