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

Neurofibromatosis Type 1 (NF1) is a common tumour predisposition syndrome characterised by neurofibromas – Nf1 ^-/- Schwann cell (SC)-derived tumours 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 tumours, but the mechanisms remained unknown. Here, we identify macrophage-secreted TGF-β as the microenvironmental injury signal that is essential for tumourigenesis. Analysis of the earliest stages of neurofibroma formation showed that tumours arise from a population of Nf1 ^-/- SCs that ‘escape’ the regenerating nerve shortly after injury. Here, they reside in a distinct microenvironment conducive for tumourigenesis, 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 tumour formation, highlighting the potential to normalise Nf1 ^-/- SCs and identifying TGF-β as a potential therapeutic target to both treat and prevent neurofibroma formation.