IGTP researchers identify a potential therapeutic strategy for malignant tumours associated with neurofibromatosis type 1

A research team from the Germans Trias i Pujol Research Institute (IGTP) has developed a new experimental model based on induced pluripotent stem cells (iPSCs) that makes it possible to reproduce in the laboratory the progression of tumours associated with neurofibromatosis type 1 (NF1), from benign forms to aggressive malignant tumours. The study, published in Nature Communications, also identifies a potential therapeutic strategy based on the combination of the drugs olaparib and selumetinib.

The study was led by the Hereditary Cancer and Translational Cancer Genomics and Bioinformatics groups at IGTP, in collaboration with researchers from the Catalan Institute of Oncology (ICO) - Bellvitge Biomedical Research Institute (IDIBELL) and the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) in the United States.

Neurofibromatosis type 1 is a genetic disease that predisposes people to the development of tumours of the peripheral nervous system. Although most are benign, some can progress to malignant peripheral nerve sheath tumours (MPNST), a highly aggressive type of sarcoma with few effective therapeutic options.

To study this process, the team generated a model based on genetically modified iPSCs to sequentially reproduce the molecular alterations involved in NF1 tumour progression. This system made it possible to observe how cells transition from a state resembling benign neurofibromas to more advanced stages compatible with malignant tumours.

"This work has enabled us to reproduce in the laboratory, for the first time in a highly precise way, the progression of tumours associated with neurofibromatosis type 1 from benign stages to malignant forms," explains Eduard Serra, IGTP researcher and co-senior author of the study. "This helps us to better understand the mechanisms driving this transformation and provides us with a new platform to identify potential therapeutic strategies," adds Meritxell Carrió, the other co-senior author of the study.

The results show that loss of the PRC2 complex, which is involved in epigenetic regulation, plays a key role in this malignant transformation. The researchers observed that this alteration causes a global reorganisation of genetic activity in the cells and promotes the acquisition of features associated with malignant tumours.

Using this model, the team carried out a screening of hundreds of compounds with therapeutic potential. The results identified a specific sensitivity of tumours with PRC2 alterations to PARP inhibitors, a family of drugs used in other types of cancer, such as some breast cancers. In preclinical models, the combination of olaparib and selumetinib significantly reduced tumour growth.

"The model we have developed has enabled us not only to study how malignant transformation occurs in NF1, but also to identify potential therapeutic vulnerabilities," explains Itziar Uriarte, first author of the study, which forms part of her doctoral thesis. "The results obtained with the combination of olaparib and selumetinib open up new avenues of research in tumours that currently have very few treatment options," adds Serra.

According to the researchers, the study provides a new platform to investigate the biology of MPNST and accelerate the identification of potential treatments for these tumours.

The study received funding from La Marató de TV3, the Children's Tumor Foundation (CTF) and the Instituto de Salud Carlos III.

Reference: Uriarte-Arrazola, I., Magallón-Lorenz, M., Fernández-Rodríguez, J. et al. Induced pluripotent stem cell-derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities. Nat Commun 17, 5361 (2026). DOI: doi.org/10.1038/s41467-026-73119-8

Image: Figure showing the progression from benign to malignant stages and how the different models of this progression were generated