Friday, May 23, 2025
5/23/2025
Regulation of MPNST pathogenesis by Chromosome 8 gene, UBR5 - Project Summary Neurofibromatosis type 1 (NF1) is a common neurogenetic cancer predisposition syndrome, affecting 1 in 3,000 individuals worldwide. While most of the tumors are benign neoplasms (neurofibromas, low-grade gliomas), 10-13% of patients will develop an aggressive sarcoma, termed a malignant peripheral nerve sheath tumor (MPNST). Composed of high-grade neoplastic Schwann cells, MPNST most often arise from a benign precursor lesion, such as plexiform neurofibroma (PN). Unfortunately, even with aggressive multi-modality therapy, these cancers recur in >50% of individuals, and most patients die within five years of diagnosis. For this reason, there is an unmet need for better therapeutic modalities. To identify novel targets, we generated a series of patient-derived xenografts (PDX) lines that more accurately reflect the molecular heterogeneity of human MPNSTs. Using these PDX lines, we showed that MPNST exhibit a high degree of aneuploidy and harbor gains involving the long arm of chromosome 8 (Chr8q). Detailed analysis of Chr8q genes revealed that UBR5 is the most highly upregulated gene in MPNST and that UBR5 genetic knockdown (KD) decreased MPNST proliferation, survival, and migration. Based on these exciting data, we hypothesize that UBR5 is a key driver of MPNST pathogenesis and in part responsible for Chr8 gain-mediated MPNST malignant progression. In this proposal, we will: (1) Define when in MPNST progression Chr8q gain occurs and if UBR5 expression through this molecular event correlates with worse overall survival. (2) Utilize a recently developed human induced pluripotent stem cell plexiform model and a murine Nf1 mutant plexiform neurofibroma-prone strain that develops MPNST following lentiviral manipulation of other genomic drivers to determine the sufficiency of UBR5 to promote MPNST formation. (3) Determine the mechanism of action of UBR5 in MPNST including how UBR5 regulates cell survival and whether its role is dependent on its E3 ubiquitin ligase activity. The experiments outlined in this proposal will provide a deeper understanding of the molecular pathogenesis of MPNST, which is required to uncover new opportunities for the development of novel therapeutic strategies that may improve clinical outcomes.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).