Cameron Church, Christian X Fay, Emil Kriukov, Hui Liu, Ashley Cannon, Lauren Ashley Baldwin, David K Crossman, Bruce Korf, Margaret R Wallace, Andrea M Gross, Brigitte C Widemann, Robert A Kesterson, Petr Baranov, Deeann Wallis | Acta Neuropathologica Communications| 2024
Abstract
Neurofibromatosis Type 1 (NF1) is caused by loss-of-function variants in the NF1 gene, with most patients developing cutaneous neurofibromas (cNFs). Selumetinib, a MEK inhibitor, is the only approved NF1 therapy, yet its effects on tumor composition and intercellular signaling remain unclear. We performed single-nucleus RNA-seq on paired cNF biopsies from four individuals, collected before and during selumetinib treatment, profiling 11,545 nuclei and over 30,000 genes. Major cell types—including Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two endothelial subtypes—were identified, with no significant shifts in cell proportions, likely reflecting intrinsic tumor variability. Differential expression and pathway analysis revealed decreased ERK/MAPK signaling across multiple cell types, most prominently in myeloid cells, and reduced opioid signaling in myeloid and endothelial cells, with similar trends in Schwann cells and fibroblasts. RNA velocity indicated altered cell states in Schwann cells and fibroblasts post-treatment, while Scriabin and CellChat analyses showed marked reductions in receptor–ligand interactions and extracellular matrix–related signaling (Collagen, Laminin, Fibronectin, Nectin). These findings define cell type–specific transcriptional and communication changes in cNFs following selumetinib treatment, offering potential biomarkers and mechanistic insights to guide future NF1 therapies.
