Induced pluripotent stem cell–derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities
Neurofibromatosis Type 1 (NF1) predisposes to peripheral nerve tumor development. The progression from a benign plexiform neurofibroma (PNF) towards a deadly malignant peripheral nerve sheath tumor (MPNST) is not completely understood but commonly involves the sequential loss of NF1, CDKN2A, and polycomb repressive complex 2 (PRC2). Here we use an iPSC-derived neural crest (NC) model to reproduce this malignant transformation through gene editing. NF1-CDKN2A double-knockout (2KO) NCs form neurofibroma-like tumors in vivo, requiring inactivation of p14ARF and p16INK4a. Additional PRC2 loss (3KO) disrupts pluripotency and induces mesenchymal stem cell-like features. 3KO NCs undergo global chromatin reorganization that prevents gliogenesis by SOX10 silencing and activates neuro-mesenchymal transcriptional programs recapitulating PNF-ANNUBP-MPNST progression. Upon nerve engraftment, 3KO NC spheres form MPNST-like tumors in vivo, mimicking an early-stage MPNST. Furthermore, we use the 3D NC spheroid models to discover drugs targeting MPNSTs through high-throughput screening of epigenetic compounds. Poly(ADP-ribose) polymerase inhibitors (PARPi) exhibit selective efficacy in PRC2-deficient NC spheroids and Olaparib-Selumetinib combination is well tolerated and significantly suppresses tumor growth in a human MPNST PDX mouse model. Malignant peripheral nerve sheath tumors (MPNST) often develop from NF1-associated lesions. Here, the authors discover that an induced pluripotent stem cells-derived NF1-CDKN2A-PRC2-deficient model mimics MPNSTs glial-to-neuro-mesenchymal transition, can form MPNST-like tumors, and be used for drug combinations discovery.
Authors
- Marc Ferrer (ORCID: https://orcid.org/0000-0003-4569-9137)
- Kelli M. Wilson (ORCID: https://orcid.org/0000-0003-2636-2766)
- Emily Lee
- Eduard Serra (ORCID: https://orcid.org/0000-0003-2895-9857)
- Helena Mazuelas (ORCID: https://orcid.org/0000-0001-7212-2144)
- Miriam Magallón‐Lorenz (ORCID: https://orcid.org/0000-0003-2741-4572)
- Jiajing Zhang (ORCID: https://orcid.org/0000-0001-7918-1040)
- Bernat Gel (ORCID: https://orcid.org/0000-0001-8878-349X)
- Katlin Recabo
- Juana Fernández‐Rodríguez (ORCID: https://orcid.org/0000-0002-7760-5804)
- Conxi Lázaro (ORCID: https://orcid.org/0000-0002-7198-5906)
- Meritxell Carrió (ORCID: https://orcid.org/0000-0002-1258-6593)
- Ignacio Blanco (ORCID: https://orcid.org/0000-0002-7414-7481)
- Itziar Uriarte-Arrazola (ORCID: https://orcid.org/0000-0002-2600-673X)
- Héctor Salvador (ORCID: https://orcid.org/0000-0002-5984-6882)
- Judit Farrés-Casas
- Crystal McKnight
- Edgar Creus-Bachiller
- Sara Ortega-Bertran
- Cleofé Romagosa
Institutions
- Hospital Sant Joan de Déu Barcelona (ES)
- Bellvitge University Hospital (ES)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- Departament de Salut (ES)
- Ajuntament de L’Hospitalet (ES)
- Institut Català d'Oncologia (ES)
- Vall d'Hebron Hospital Universitari (ES)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
- National Center for Advancing Translational Sciences (US)
- Hospital Universitari Germans Trias i Pujol (ES)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-17
- DOI
- https://doi.org/10.1038/s41467-026-73119-8
- Primary Topic
- Neurofibromatosis and Schwannoma Cases
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Children's Tumor Foundation
- Fundació la Marató de TV3
- Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya
- Instituto de Salud Carlos III
- National Center for Advancing Translational Sciences
- Congressionally Directed Medical Research Programs