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2026-06-17

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cc-by-nc-nd (c) Uriarte-Arrazola, I. et al., 2026
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/232303

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

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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.

Recurs relacionat

https://doi.org/10.1038/s41467-026-73119-8

Matèries

Neurofibromatosi, Tumors

Matèries (anglès)

Neurofibromatosis, Tumors

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Articles publicats en revistes (Fonaments Clínics)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

URIARTE ARRAZOLA, Itziar, et al. Induced pluripotent stem cell-derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities. Nature Communications. 2026. Vol. 17. ISSN 2041-1723. [consulted: 2 of November of 2026]. Available at: https://hdl.handle.net/2445/232303

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