Glial-to-mesenchymal transition of tumor Schwann cells drives the genetic burden in MPNSTs from neurofibromatosis type 1 mouse model.

There is currently no effective treatment for malignant peripheral nerve sheath tumors (MPNSTs), half of which result from malignant progression of neurofibromas (NFs) in patients with neurofibromatosis type 1 (NF1). NFs are due to biallelic loss-of-function of NF1, which negatively regulates the RAS pathway, in the Schwann cell lineage. We generated a conditional Nf1-mutant mouse model where NFs spontaneously transform into MPNSTs, faithfully recapitulating the human situation. Single-cell transcriptomic profiling demonstrated progression of NFs into MPNSTs, with a glial-to-mesenchymal transition. Sox9 was identified as a marker of this transition and key player in tumor growth. The transition is followed by a loss of the tumor suppressor gene (TSG) Cdkn2a and acquisition of pathogenic variants of other TSGs. Finally, a proof-of-concept drug screen aimed at reducing Sox9 expression in tumor cells identified 12 FDA-approved drugs. Notably, several of these agents target the RAS signaling cascade, suggesting that multi-targeted inhibition of this pathway may represent a promising therapeutic strategy against MPNSTs.