College of Bioinformatics Science and Technology, Harbin Medical University, China.
Mol Oncol. 2019 Dec;13(12):2588-2603. doi: 10.1002/1878-0261.12569. Epub 2019 Sep 17.
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.
胶质母细胞瘤（GBM）是最常见且侵袭性最强的原发性脑肿瘤，其中 GBM 干细胞（GSCs）被认为有助于形成侵袭性表型和不良预后。然而，GSCs 如何发展为侵袭性细胞在很大程度上仍未得到探索。在这里，我们揭示了具有不同功能状态的细胞亚群，以及在异质性原发性 GBM 肿瘤中存在具有高侵袭潜力的细胞。我们通过对单个肿瘤细胞进行伪时间排序来重建分支轨迹，其中根显示出 GSC 样表型，而末端则显示出高侵袭活性。因此，我们进一步确定了一条 GSCs 逐渐转化为侵袭性细胞的途径，称为“干细胞到侵袭途径”。在这条途径上，细胞表现出 GBM 侵袭相关特征的递增表达，而 GBM 干细胞标志物的表达则逐渐减少。这些发现在 GBM 的另一个独立单细胞数据集得到了验证。通过分析该途径下的分子级联反应，我们确定了控制肿瘤细胞获得侵袭潜力的关键因素，包括转录因子和长非编码 RNA。我们的工作为 GBM 的进展提供了新的见解，特别是为原发性肿瘤细胞获得侵袭潜力提供了新的见解，并支持癌症干细胞模型，这对 GBM 的治疗具有重要意义。
