NFS-20. DECIPHERING CELLULAR CROSSTALK IN PERIPHERAL NERVOUS SYSTEM TUMORS ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1 THROUGH SINGLE-CELL RNA SEQUENCING

Neurofibromatosis Type 1 (NF1) is a genetic disorder characterized by mutations and dysfunctional expression of neurofibromin 1 gene, a critical tumor-suppressor gene. NF1’s complex pathophysiology involves dysregulation of the RAS-MAPK signaling pathway, resulting in sustained MAPK signaling. Among others, the spectrum of clinical features includes low-grade tumors (e.g. plexiform neurofibromas (pNFs)) and malignant peripheral nerve sheath tumors (MPNST). While surgical removal of peripheral nerve tumors is common, total resection is often unattainable. Additionally, approved therapies comprising MEK inhibitors fail to prevent malignization, highlighting the urgent need for novel targets for effective therapies. To explore novel potential targets across a broad spectrum, we analyzed published scRNA-seq datasets (Kershner et al. 2021, Wu et al. 2022) from human patients, including pNFs and MPNSTs. We further investigated key pathways in vitro with patient-derived cell culture models. ScRNA-seq provides insight into complex networks of cell-to-cell interactions that drive the malignant phenotype of cancerous tissues. Due to the rich presence of ECM in NF1 tumors we aimed to investigate cell types contributing to key extracellular matrix (ECM) components and associated signaling pathways. Analysis of 19 NF1 tumor samples revealed consistent presence of Schwann cells (SCs), fibroblasts, endothelial cells, and immune cells. Proliferating cells were found in MPNSTs, while pericytes were exclusive to pNFs. We compared secreted and ECM signaling between the cell types of both tumors. Our analysis discovered, among other findings, collagen signaling, highlighting fibroblasts as emitters and SCs as receivers. We further confirmed these findings through culturing of NF1-derived cells in vitro with and without collagen, observing increased cell proliferation in the presence of collagen. Further experiments and analyses are ongoing. The emphasis on ECM and signaling adds depth to our understanding of NF1 pathogenesis and suggests potential therapeutic targets.