Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the Hippo pathway [Research Articles]

Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor-suppressor Neurofibromin, a negative regulator of RAS signaling. NF1 patients present with a wide range of clinical manifestations and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that Hoxb7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the Hoxb7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a "modifier" for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today.

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