The transcriptomic signature of painful and non-painful human NF2 schwannomas [set1]

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. Overall design: Examined the transcriptomic differences of formalin fixed, paraffin-embedded (FFPE) painful (n=3 total) and non-painful (n=8 total) peripheral human NF2-schwannomas (Benign Nerve Sheath tumors).

神经鞘瘤（Schwannoma）是一类良性外周神经鞘瘤，可引发包括重度持续性疼痛在内的多种显著并发症。当前治疗手段仅局限于手术切除，且本身伴随较高不良事件风险，同时多数患者无法获得有效的肿瘤相关性疼痛缓解。因此，阐明神经鞘瘤诱发疼痛的分子机制，是开发新型治疗方案的首要迫切需求。
本研究针对小样本队列的2型神经纤维瘤病（NF2）患者来源的福尔马林固定石蜡包埋（FFPE）伴痛与无痛神经鞘瘤样本，开展了下一代RNA测序（RNA-seq）。对基因及异构体水平的差异表达分析显示，伴痛与无痛肿瘤间存在显著的转录组学差异；差异调控基因包含成纤维细胞生长因子（FGF）家族成员。通过人源NF2异种移植模型，本研究证实神经鞘瘤细胞中FGF7的过表达与痛觉样行为的发生相关。本研究结果既证实了福尔马林固定样本应用RNA测序的可行性与价值，同时也揭示了一条全新的肿瘤相关性疼痛致病通路。
实验整体设计：对福尔马林固定石蜡包埋（FFPE）的外周人源NF2神经鞘瘤（良性神经鞘瘤，Benign Nerve Sheath Tumors）样本进行转录组学差异分析，其中伴痛样本共3例，无痛样本共8例。