神经纤维瘤1型（NF1）患者易于发展丛状神经纤维瘤（PNFs）。三种内质网（ER）应激响应途径可恢复细胞稳态。未折叠蛋白质应答（UPR）感应器在许多癌症的肿瘤启动中起作用。我们发现，所有三个UPR通路在小鼠和人类PNFs中均被激活，蛋白激酶RNA [PKR]-样ER激酶（PERK）表达最高。我们测试了神经纤维瘤细胞是否适应ER应激，导致其生长。 PERK的药理或基因抑制减少了小鼠神经纤维瘤球数量，并且在天鹅绒细胞前体细胞（SCPs）中基因抑制PERK减少了细胞移植模型中的肿瘤样病变数量。此外，在PNF小鼠模型中，删除天鹅绒细胞（SCs）和SCPs中的PERK减少了肿瘤大小、数量，并增加了存活率。机械上，Nf1的丧失激活了PERK-eIF2α-ATF4信号转导，并增加了ATF4下游靶基因p21从细胞核到细胞质的转位。这种细胞核-细胞质的转位是由exportin-1介导的。Runx通过转录激活核糖体基因表达并增加蛋白质合成，使SCs能够适应ER应激和肿瘤形成。我们提出定位蛋白稳态可能为PNFs提供细胞毒性和/或可能持久的新疗法。©2023。作者（S）已经独家许可给Springer Nature Limited。

Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.