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

Abstract

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. <i>Sox9</i> 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) <i>Cdkn2a</i> and acquisition of pathogenic variants of other TSGs. Finally, a proof-of-concept drug screen aimed at reducing <i>Sox9</i> 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.