对于了解儿童脑肿瘤的细胞起源是理解肿瘤起始和确定特定于祖细胞系的治疗靶点的关键。以往的映射起源细胞的策略通常涉及将人类肿瘤与小鼠胚胎组织进行对比，但由于物种特异性差异的存在，这种方法可能存在局限性。本研究旨在利用正在发育的人类小脑图解，揭示三种最常见的儿童脑肿瘤，即室管膜瘤、脉络丛星形细胞瘤和髓母细胞瘤的细胞起源。我们利用由176,645个细胞组成的正常发育人类小脑单细胞图解作为参考，通过基因集变异分析、相关性和单细胞匹配技术，与4,416个样本和单细胞转录组肿瘤数据进行深入比较。 我们发现星形胶质细胞小脑系列可能是后颅窝室管膜瘤的起源。我们提出，颅下星形胶质细胞瘤来源于少突胶质细胞系，并且MHC II基因在这些肿瘤中特异富集。我们证实SHH和3/4组髓状细胞瘤来源于颗粒细胞和单棘刷细胞系列。放射线诱导的胶质瘤起源于小脑胶质系列，并且与原发性髓状细胞瘤具有不同的起源。我们确定了在起源细胞系列中表达的肿瘤基因和肿瘤特异性基因；这两组基因都代表了未来研究中有希望的治疗靶点。 根据我们的研究结果，肿瘤内的个体细胞可能呈现出局限发展细胞系列中不同细胞类型的特征。因此，我们认为肿瘤可以起源于小脑“起源细胞系列”中的多个细胞状态。 © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Distinguishing the cellular origins of childhood brain tumors is key for understanding tumor initiation and identifying lineage-restricted, tumor-specific therapeutic targets. Previous strategies to map the cell-of-origin typically involved comparing human tumors to murine embryonal tissues, which is potentially limited due to species-specific differences. The aim of this study was to unravel the cellular origins of the three most common pediatric brain tumors, ependymoma, pilocytic astrocytoma, and medulloblastoma, using a developing human cerebellar atlas.We used a single-nucleus atlas of the normal developing human cerebellum consisting of 176,645 cells as a reference for an in-depth comparison to 4,416 bulk and single-cell transcriptome tumor datasets, using gene set variation analysis, correlation, and single-cell matching techniques.We find that the astroglial cerebellar lineage is potentially the origin for posterior fossa ependymomas. We propose that infratentorial pilocytic astrocytomas originate from the oligodendrocyte lineage and MHC II genes are specifically enriched in these tumors. We confirm that SHH and Group 3/4 medulloblastomas originate from the granule cell and unipolar brush cell lineages. Radiation-induced gliomas stem from cerebellar glial lineages and demonstrate distinct origins from the primary medulloblastoma. We identify tumor genes that are expressed in the cerebellar lineage of origin, and genes that are tumor specific; both gene sets represent promising therapeutic targets for future study.Based on our results, individual cells within a tumor may resemble different cell types along a restricted developmental lineage. Therefore, we suggest that tumors can arise from multiple cellular states along the cerebellar "lineage of origin".© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.