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

TY - JOUR

T1 - Glial-to-mesenchymal transition of tumor Schwann cells drives the genetic burden in MPNSTs from neurofibromatosis type 1 mouse model

AU - Radomska, Katarzyna J.

AU - Onfroy, Audrey

AU - Lecerf, Laure

AU - Job, Bastien

AU - Beaude, Aurélien

AU - Sanz, Laura Sesma

AU - Jalkh, Tatiana El

AU - Thieffry, Denis

AU - Charnay, Patrick

AU - Wolkenstein, Pierre

AU - Ortonne, Nicolas

AU - Coulpier, Fanny

AU - Topilko, Piotr

N1 - Publisher Copyright: copyright © 2025 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. distributed under a creative commons Attribution Noncommercial license 4.0 (cc BY-Nc).

PY - 2025/11

Y1 - 2025/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105021551429

U2 - 10.1126/sciadv.adt9210

DO - 10.1126/sciadv.adt9210

M3 - Article

C2 - 41223283

AN - SCOPUS:105021551429

SN - 2375-2548

VL - 11

JO - Science Advances

JF - Science Advances

IS - 46

M1 - eadt9210

ER -