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. <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.
Authors
- Tatiana El Jalkh (ORCID: https://orcid.org/0000-0002-6989-4132)
- P. Wolkenstein (ORCID: https://orcid.org/0000-0001-8194-457X)
- Piotr Topilko (ORCID: https://orcid.org/0000-0001-7381-6770)
- Bastien Job (ORCID: https://orcid.org/0000-0002-2720-7664)
- Patrick Charnay (ORCID: https://orcid.org/0000-0002-3847-6042)
- Laura Sesma-Sanz (ORCID: https://orcid.org/0000-0001-7792-1631)
- Laure Lecerf (ORCID: https://orcid.org/0000-0001-8342-5298)
- Katarzyna J. Radomska (ORCID: https://orcid.org/0000-0001-8243-0669)
- Denis Thieffry (ORCID: https://orcid.org/0000-0003-0271-1757)
- Nicolás Ortonne (ORCID: https://orcid.org/0000-0003-0111-7422)
- Aurélien Beaude (ORCID: https://orcid.org/0000-0001-7199-5242)
- Fanny Coulpier (ORCID: https://orcid.org/0009-0007-7638-3676)
- Audrey Onfroy (ORCID: https://orcid.org/0009-0003-1429-4230)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of Dundee (GB)
- Institut Gustave Roussy (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- National Phenotypic Screening Centre (GB)
- Institut de Biologie de l'École Normale Supérieure (FR)
- Hôpitaux Universitaires Henri-Mondor (FR)
- Institut Mondor de Recherche Biomédicale (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2025-11-12
- DOI
- https://doi.org/10.1126/sciadv.adt9210
- Citations
- 1
- Primary Topic
- Neurofibromatosis and Schwannoma Cases
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- Fondation Maladies Rares
- Institut National de la Santé et de la Recherche Médicale