A study by the Clinical Genomics Unit (UGC) at IGTP has created a new cell model. This model aims to advance research into NF2-related schwannomatosis (SWN-NF2), a rare genetic disease.
The research, published in Genes & Disease, details the creation of cell spheroids. These spheroids are derived from induced pluripotent stem cells (iPSC), which can transform into almost any cell type. The spheroids replicate the alterations seen in tumors associated with SWN-NF2.
SWN-NF2 is an autosomal dominant syndrome caused by mutations in the NF2 gene. It affects approximately 1 in every 28,000 births worldwide. The condition is characterized by vestibular schwannomas, often with other schwannomas, meningiomas, and ependymomas.
The mutation occurs in a non-sex-linked gene. A single altered copy, inherited from either parent, is enough for the condition to manifest. Research has been hindered by a lack of reliable human cell models that accurately mimic tumor development.
The research team created several cell models derived from human stem cells. Six different lines were generated using patient samples and CRISPR/Cas9 gene-editing. Three lines had a single NF2 gene mutation, mimicking affected individuals. Three had alterations in both copies of the gene, as seen in tumor cells.
For the first time, these stem cells were differentiated into Schwann cells, the cell type involved in the disease. This was achieved using a three-dimensional system that produces cellular structures (spheroids). These spheroids carry the same mutations found in patients' tumors.
These structures were thoroughly analyzed and shown to share genetic and functional features with real tumor cells. The findings confirmed that they reproduce the molecular changes found in tumors from NF2 patients. This includes the abnormal activation of previously described cellular mechanisms.
"This model provides an innovative and faithful tool to study the role of the NF2 gene under controlled conditions and to evaluate new therapeutic strategies," says Dr. Elisabeth Castellanos. "Moreover, the pluripotency of these cells opens the door to studying other cell types and tumors associated with the disease."
This cell system offers a stable and reproducible platform to further understand the disease. It can also help develop preclinical assays in a physiologically relevant context. The model may also be useful for investigating other NF2-related tumors beyond schwannomas.
The generated cell lines will be made available to the scientific community. This aims to promote collaborative research in this field. The project was supported by patient associations through sample donation and partial funding.