Induced pluripotent stem cell-derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities

  • Nat Commun. 2026 Jun 17;17(1):5361. doi: 10.1038/s41467-026-73119-8.
Itziar Uriarte-Arrazola  1 ,  Míriam Magallón-Lorenz  2 ,  Juana Fernández-Rodríguez  3  4  5  6 ,  Jiajing Zhang  7 ,  Emily Lee  7 ,  Sara Ortega-Bertran  3  4 ,  Edgar Creus-Bachiller  3  4 ,  Judit Farrés-Casas  1 ,  Kelli M Wilson  8 ,  Crystal McKnight  8 ,  Katlin Recabo  8 ,  Ignacio Blanco  9 ,  Héctor Salvador  10 ,  Cleofé Romagosa  11 ,  Conxi Lázaro  3  4  6 ,  Helena Mazuelas  1 ,  Bernat Gel  12  13 ,  Marc Ferrer  14 ,  Meritxell Carrió  15 ,  Eduard Serra  16  17
Affiliations
  • 1. Hereditary Cancer Group, CARE Program, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain.
  • 2. Translational Bioinformatics and Genomics of Cancer, CARE Program, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain.
  • 3. Hereditary Cancer Program, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
  • 4. Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
  • 5. Mouse Lab, SCT-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
  • 6. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
  • 7. 3D Tissue Bioprinting Laboratory, Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), Rockville, MD, USA.
  • 8. Compound Management, Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), Rockville, MD, USA.
  • 9. Clinical Genetics Department, Laboratori Clínic de la Metropolitana Nord, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain.
  • 10. Pediatric Oncology Department, Sant Joan de Déu Barcelona Children's Hospital, Barcelona, Spain.
  • 11. Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
  • 12. Translational Bioinformatics and Genomics of Cancer, CARE Program, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain. [email protected].
  • 13. Departament de Fonaments Clínics, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain. [email protected].
  • 14. 3D Tissue Bioprinting Laboratory, Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), Rockville, MD, USA. [email protected].
  • 15. Hereditary Cancer Group, CARE Program, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain. [email protected].
  • 16. Hereditary Cancer Group, CARE Program, Germans Trias i Pujol Research Institute (IGTP), Barcelona, Spain. [email protected].
  • 17. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [email protected].
PMID: 42310314 DOI: 10.1038/s41467-026-73119-8
Abstract

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.

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