Glioblastoma (GBM) is the most common and aggressive primary brain tumor, in which GBM stem cells (GSCs) were identified to contribute to aggressive phenotypes and poor prognosis. Yet, how GSCs progress to invasive cells remains largely unexplored. Here, we revealed the cell subpopulations with distinct functional status and the existence of cells with high invasive potential within heterogeneous primary GBM tumors. We reconstructed a branched trajectory by pseudotemporal ordering of single tumor cells, in which the root showed GSC-like phenotype while the end displayed high invasive activity. Thus, we further determined a path along which GSCs gradually transformed to invasive cells, called the 'stem-to-invasion path'. Along this path, cells showed incremental expression of GBM invasion-associated signatures and diminishing expression of GBM stem cell markers. These findings were validated in an independent single-cell data set of GBM. Through analyzing the molecular cascades underlying the path, we identify crucial factors controlling the attainment of invasive potential of tumor cells, including transcription factors and long noncoding RNAs. Our work provides novel insights into GBM progression, especially the attainment of invasive potential in primary tumor cells, and supports the cancer stem cell model, with valuable implications for GBM therapy.

中文翻译：

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单细胞RNA序列揭示了胶质母细胞瘤进展的侵入性轨迹和分子级联。

胶质母细胞瘤（GBM）是最常见和侵略性的原发性脑肿瘤，其中GBM干细胞（GSC）被确定有助于侵袭性表型和不良预后。然而，GSC如何发展为侵袭性细胞仍大有待探索。在这里，我们揭示了具有不同功能状态的细胞亚群，以及异质原发性GBM肿瘤中具有高侵袭潜力的细胞的存在。我们通过单个肿瘤细胞的伪时间顺序重建了一条分支轨迹，其中根显示出GSC样表型，而末端显示出高侵袭活性。因此，我们进一步确定了GSCs逐渐转化为侵袭性细胞的路径，称为“干向侵袭路径”。沿着这条路 细胞显示GBM入侵相关签名的增量表达和GBM干细胞标志物的递减表达。这些发现在GBM的独立单细胞数据集中得到了验证。通过分析路径的分子级联，我们确定了控制肿瘤细胞侵袭潜能实现的关键因素，包括转录因子和长非编码RNA。我们的工作为GBM进展提供了新颖的见解，尤其是在原发性肿瘤细胞中获得了潜在的侵袭性，并支持了癌症干细胞模型，对GBM治疗具有重要意义。我们确定了控制肿瘤细胞侵袭潜能获得的关键因素，包括转录因子和长非编码RNA。我们的工作为GBM进展提供了新颖的见解，尤其是在原发性肿瘤细胞中获得了潜在的侵袭性，并支持了癌症干细胞模型，对GBM治疗具有重要意义。我们确定了控制肿瘤细胞侵袭潜能获得的关键因素，包括转录因子和长非编码RNA。我们的工作为GBM进展提供了新颖的见解，尤其是在原发性肿瘤细胞中获得了潜在的侵袭性，并支持了癌症干细胞模型，对GBM治疗具有重要意义。