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

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

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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