An Orthotopic Sciatic Nerve Xenograft for Neurofibromatosis Type 1 Neurofibromas

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by pathogenic variants in the NF1 gene, leading to the loss of neurofibromin function and the development of benign peripheral nerve sheath tumors known as neurofibromas. While genetically engineered mouse models (GEMMs) have advanced our understanding of NF1 pathophysiology, they often fail to replicate the spontaneous tumorigenesis and microenvironmental complexity of patient-derived neurofibromas. A key challenge in modeling benign neurofibromas is their dependency on the nerve microenvironment, which conventional xenograft approaches do not recapitulate. Here, an optimized orthotopic xenograft model was developed for NF1-associated neurofibromas. Using intraneural injection of immortalized neurofibroma-derived human Schwann cells into the sciatic nerve of NSG immunodeficient mice, this model recapitulates key features of human neurofibroma biology, including nerve-dependent growth and tumor microenvironment interactions. This protocol allows dynamic, real-time monitoring of tumor progression via bioluminescence imaging, providing a reproducible and quantitative method to assess neurofibroma growth. Unlike GEMMs, this model allows for controlled tumor initiation and precise evaluation of preclinical therapeutic strategies. Additionally, it serves as a bridge between GEMMs and patient-derived xenograft models, enhancing the translational relevance of neurofibroma research. By offering a physiologically relevant setting for studying tumor-nerve interactions, this model provides a valuable platform for investigating neurofibroma biology and evaluating potential therapeutic interventions. Future refinements, including the integration of immune components or advanced imaging techniques, may further enhance its application to NF1 research.