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bioRxiv · 10.1101/2025.08.13.670072

iPSC-derived NF1-CDKN2A-PRC2 deficient neural crest cells mimic glial-to-neuro-mesenchymal transition and form MPNST-like tumors in vivo

Uriarte-Arrazola, I.·Magallon-Lorenz, M.·Fernandez-Rodriguez, J.·Farres-Casas, J.·Ortega-Bertran, S.·Creus-Bachiller, E.·Romagosa, C.·Lazaro, C.·Mazuelas, H.·Gel, B.·Carrio, M.·Serra, E.
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Abstract

Neurofibromatosis Type 1 (NF1) predisposes to peripheral nerve tumor development. Commonly, the progression from a benign plexiform neurofibroma (PNF) towards a deadly malignant peripheral nerve sheath tumor (MPNST) involves a poorly understood glial-to-mesenchymal transition and the sequential loss of NF1, CDKN2A, and polycomb repressive complex 2 (PRC2). Using an iPSC-derived neural crest (NC) model, we reproduced this malignant transformation through gene editing. NF1-CDKN2A double-knockout (2KO) NCs retained glial differentiation capacity and formed neurofibroma-like tumors in vivo, requiring inactivation of p14ARF and p16INK4a. Additional PRC2 loss (3KO) disrupted pluripotency and induced mesenchymal stem cell-like features in iPSCs an NCs. 3KO NCs suffered a global chromatin reprograming that silenced SOX10 preventing gliogenesis and activated neuro-mesenchymal programs. Gene signatures characterizing this glial-to-neuro-mesenchymal transition were recapitulated in human PNF-ANNUBP-MPNST tumors. 3KO NC spheres formed MPNST-like tumors in vivo upon nerve engraftment, genuinely mimicking an early-stage MPNST. We used the developed 3D NC spheroid models for the discovery of drugs targeting MPNSTs by performing a high-throughput screening of an epigenetic compound library. We found that poly(ADP-ribose) polymerase inhibitors (PARPi) exhibit selective efficacy in PRC2-deficient NC spheroids. We confirmed that Olaparib-Selumetinib combination in a MPNST PDX mouse model was well tolerated and significantly suppressed tumor growth.

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Uriarte-Arrazola, I., Magallon-Lorenz, M., Fernandez-Rodriguez, J., Farres-Casas, J., Ortega-Bertran, S., Creus-Bachiller, E., Romagosa, C., Lazaro, C., Mazuelas, H., Gel, B., Carrio, M., Serra, E.. 2025-08-15. iPSC-derived NF1-CDKN2A-PRC2 deficient neural crest cells mimic glial-to-neuro-mesenchymal transition and form MPNST-like tumors in vivo. https://doi.org/10.1101/2025.08.13.670072

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