Deciphering the Role of NF1 in Schwann Cell Differentiation and Tumorigenesis Using Novel Models of Humanized Neurofibroma and MPNST
Abstract
The tumor predisposition von Recklinghausen’s Neurofibromatosis type I (NF1) is one of the most common genetic disorders of the nervous system, affecting 1 in 3,000 individuals. Cutaneous and plexiform neurofibromas, as well as malignant peripheral nerve sheath tumors, are serious complications of NF1. Neurofibromas are complex peripheral nerve tumors and are composed mainly of abnormal local cells, including Schwann cells, nerves, endothelial cells, fibroblasts, and large numbers of infiltrating mast cells and macrophages. Currently, little is known about the mechanisms mediating the initiation and progression of these tumors or the identity of the specific cell type that gives rise to neurofibromas. Recent work in our laboratory has identified the developmental cells of origin for cutaneous and plexiform neurofibroma and generated novel mouse models for these complex NF1-associated tumors. These valuable reagents have begun yielding vital clues to understand early events that dictate neurofibromagenesis. The knowledge that we learned from these models will now guide us and allow us for the first time to capitalize on the latest advances in the field of human iPS cells with CRISPR/Case9 gene editing and our expertise in Schwann cell biology, as well as our ability in creating and exploitation of novel Neurofibromatosis models to generate human-derived neurofibroma and MPNST for testing of potential therapeutics that will halt or delay tumor progression to develop personalized therapies for NF1 patients. Furthermore, these models will allow us to monitor the evolution of human tumorigenesis from NF1 patient-derived iPSCs to neural crest stem cells to Schwann cells to neurofibroma to MPNSTs, which permits the study of cellular functions at different stages of tumor development, while existing models will not permit us to do so. Therefore, our studies proposed in this application should lead to the identification and elucidation of novel mechanisms governing neurofibroma and MPNST development, which may lead directly to specific and potentially effective therapeutics for these tumors where none exists today.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910687
Entities
People
- Juan Mo
Organizations
- United States Army
- University of Texas Southwestern Medical Center