Stem-like cells drive NF1-associated MPNST functional heterogeneity and tumor progression

NF1-associated malignant peripheral nerve sheath tumors (MPNST) are the major cause of mortality in neurofibromatosis. MPNST arise from benign peripheral nerve plexiform neurofibromas (PN) which originate in the embryonic neural crest cell lineage. Using reporter transgenes that label early neural crest lineage cells in multiple NF1 MPNST mouse models, we discovered and characterized a rare MPNST cell population with stem cell-like properties that is essential for tumor initiation and relapse. Following isolation of these cells we derive a cancer stem cell specific gene expression signature that includes consensus embryonic neural crest genes and we also identify Nestin as a novel marker for the MPNST cell of origin. Finally, application of the mouse cancer stem cell signature to single cell sequencing data from a rare NF1-associated MPNST precursors called atypical neurofibromatosis neoplasms of uncertain biologic potential (ANNUBP), identifies preformed unsupervised gene expression cell clusters. Enrichment of the cancer stem cell signature in cognate human tumors supports the generality and relevance of cancer stem cells to therapy development. Overall design: Single-cell transcriptomic profiling of human ANNUBP

NF1相关恶性外周神经鞘膜瘤（MPNST）是神经纤维瘤病患者的主要致死原因。MPNST起源于良性外周神经丛状神经纤维瘤（PN），而后者源自胚胎神经嵴细胞谱系。本研究利用可标记多种NF1相关MPNST小鼠模型中早期神经嵴谱系细胞的报告转基因，发现并鉴定出一类罕见的、具有干细胞样特性的MPNST细胞群，该细胞群对于肿瘤起始与复发至关重要。分离此类细胞后，我们构建了癌症干细胞特异性基因表达特征谱，其包含共识性胚胎神经嵴相关基因，同时还鉴定出巢蛋白（Nestin）作为MPNST起源细胞的新型标志物。最后，将小鼠癌症干细胞特征谱应用于一类罕见NF1相关MPNST前体——生物学潜能未明确的非典型神经纤维瘤病肿瘤（ANNUBP）的单细胞测序数据，成功识别出预先形成的无监督基因表达细胞簇。该癌症干细胞特征在对应人类肿瘤中的富集情况，证实了癌症干细胞与治疗开发的相关性及普遍性。整体实验设计：人类ANNUBP的单细胞转录组谱分析。