Clinically unfavorable transcriptome subtypes of non-WNT/non-SHH medulloblastomas are associated with a predominance in proliferating and progenitor-like cell subpopulations

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-06-07 DOI:10.1007/s00401-024-02746-6
Konstantin Okonechnikov, Daniel Schrimpf, Jan Koster, Philipp Sievers, Till Milde, Felix Sahm, David T. W. Jones, Andreas von Deimling, Stefan M. Pfister, Marcel Kool, Andrey Korshunov
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Abstract

The non-WNT/non-SHH (Grp3/Grp4) medulloblastomas (MBs) include eight second-generation subgroups (SGS; I–VIII) each with distinct molecular and clinical characteristics. Recently, we also identified two prognostically relevant transcriptome subtypes within each SGS MB, which are associated with unique gene expression signatures and signaling pathways. These prognostic subsets may be in connection to the intra-tumoral cell landscape that underlies SGS MB clinical-molecular diversity. Here, we performed a deconvolution analysis of the Grp3/Grp4 MB bulk RNA profiles using the previously identified single-cell RNA-seq reference dataset and focusing on variability in the cellular composition of SGS MB. RNA deconvolution analysis of the Grp3/Grp4 MB disclosed the subgroup-specific neoplastic cell subpopulations. Neuronally differentiated axodendritic GP3-C1 and glutamatergic GP4-C1 subpopulations were distributed within Grp3- and Grp4-associated SGS MB, respectively. Progenitor GP3-B2 subpopulation was prominent in aggressive SGS II MB, whereas photoreceptor/visual perception GP3/4-C2 cell content was typical for SGS III/IV MB. The current study also revealed significant variability in the proportions of cell subpopulations between clinically relevant SGS MB transcriptome subtypes, where unfavorable cohorts were enriched with cell cycle and progenitor-like cell subpopulations and, vice versa, favorable subtypes were composed of neuronally differentiated cell fractions predominantly. A higher than median proportion of proliferating and progenitor cell subpopulations conferred the shortest survival of the Grp3 and Grp 4 MB, and similar survival associations were identified for all SGS MB except SGS IV MB. In summary, the recently identified clinically relevant Grp3/Grp4 MB transcriptome subtypes are composed of different cell populations. Future studies should aim to validate the prognostic and therapeutic role of the identified Grp3/Grp4 MB inter-tumoral cellular heterogeneity. The application of the single-cell techniques on each SGS MB separately could help to clarify the clinical significance of subgroup-specific variability in tumor cell content and its relation with prognostic transcriptome signatures identified before.

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非WNT/非SHH髓母细胞瘤的临床不利转录组亚型与增殖细胞和祖细胞亚群占优势有关。
非WNT/非SHH(Grp3/Grp4)髓母细胞瘤(MBs)包括八个第二代亚组(SGS;I-VIII),每个亚组都具有不同的分子和临床特征。最近,我们还在每个 SGS MB 中发现了两个与预后相关的转录组亚型,它们与独特的基因表达特征和信号通路相关。这些预后亚型可能与SGS MB临床分子多样性的瘤内细胞景观有关。在此,我们利用之前确定的单细胞 RNA-seq 参考数据集,对 Grp3/Grp4 MB 大量 RNA 图谱进行了去卷积分析,重点研究 SGS MB 细胞组成的变异性。Grp3/Grp4 MB的RNA解卷积分析揭示了亚组特异性肿瘤细胞亚群。神经元分化的轴突状 GP3-C1 和谷氨酸能 GP4-C1 亚群分别分布在 Grp3 和 Grp4 相关的 SGS MB 中。在侵袭性 SGS II MB 中,祖细胞 GP3-B2 亚群非常突出,而在 SGS III/IV MB 中,光感受器/视觉感知 GP3/4-C2 细胞是典型细胞。目前的研究还揭示了与临床相关的 SGS MB 转录组亚型之间细胞亚群比例的显著差异,其中不利亚型富含细胞周期和祖细胞样亚群,反之,有利亚型则主要由神经元分化细胞组成。增殖细胞亚群和祖细胞亚群的比例高于中位数,使 Grp3 和 Grp 4 MB 的存活期最短,除 SGS IV MB 外,所有 SGS MB 都有类似的存活期关联。总之,最近发现的与临床相关的Grp3/Grp4 MB转录组亚型由不同的细胞群组成。未来的研究应旨在验证已发现的 Grp3/Grp4 MB 肿瘤细胞间异质性的预后和治疗作用。对每种 SGS MB 单独应用单细胞技术有助于明确肿瘤细胞含量亚组特异性变异的临床意义及其与之前发现的预后转录组特征的关系。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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