Project description:Schwannomas are benign peripheral nerve sheath tumors that are associated with substantial morbidity including severe, persistent pain. Treatment, essentially limited to surgical resection, is associated with significant morbidity and for many patient’s efficacious treatment of tumor-related pain is not achievable. There is an urgent need to elucidate the molecular mechanisms underlying schwannoma-induced pain as a first step in development of new therapeutics. In this study, we performed next-generation RNASequencing on a small cohort of formalin fixed paraffin-embedded, painful, and non-painful schwannoma samples obtained from Neurofibromatosis type 2 (NF2) patients. Differential gene and isoform level expression analysis revealed significant transcriptomic differences between painful and non-painful tumors; differentially regulated genes included members of the fibroblast growth factor (FGF) family of genes. Using a xenograft model of human-NF2 we demonstrated that over-expression of FGF7 in schwannoma cells was associated with the development of pain-like behaviors. These results demonstrate both the value of RNASeq utilizing formalin fixed tissues and reveal a novel pathway responsible for neoplasm-associated pain.
Project description:Schwannomas are benign peripheral nerve sheath tumors that are associated with substantial morbidity including severe, persistent pain. Treatment, essentially limited to surgical resection, is associated with significant morbidity and for many patient’s efficacious treatment of tumor-related pain is not achievable. There is an urgent need to elucidate the molecular mechanisms underlying schwannoma-induced pain as a first step in development of new therapeutics. In this study, we performed next-generation RNASequencing on a small cohort of formalin fixed paraffin-embedded, painful, and non-painful schwannoma samples obtained from Neurofibromatosis type 2 (NF2) patients. Differential gene and isoform level expression analysis revealed significant transcriptomic differences between painful and non-painful tumors; differentially regulated genes included members of the fibroblast growth factor (FGF) family of genes. Using a xenograft model of human-NF2 we demonstrated that over-expression of FGF7 in schwannoma cells was associated with the development of pain-like behaviors. These results demonstrate both the value of RNASeq utilizing formalin fixed tissues and reveal a novel pathway responsible for neoplasm-associated pain.
Project description:Schwannomas are benign neoplasms that can cause gain- and loss-of-function neurological phenotypes, including severe, intractable pain. To investigate the molecular mechanisms underlying schwannoma-associated pain we compared the RNA sequencing profile of painful and non-painful schwannomas from NF2 patients. Distinct segregation of painful and non-painful tumors by gene expression patterns was observed. Differential expression analysis showed the upregulation of fibroblast growth factor 7 (FGF7) in painful schwannomas. Behavioral support for this finding was observed using a xenograft human NF2-schwannoma model in nude mice. In this model, over-expression of FGF7 in intra-sciatically implanted NF2 tumor cells generated pain behavior compared with controls.
