Cancer stem cells are critical for cancer initiation, development, and treatment resistance. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. To overcome these limitations, we performed single-cell RNA sequencing on 53586 adult glioblastoma cells and 22637 normal human fetal brain cells, and compared the lineage hierarchy of the developing human brain to the transcriptome of cancer cells. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. We also find that this progenitor population contains the majority of the cancer’s cycling cells, and, using RNA velocity, is often the originator of the other cell types. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem cells. Our analyses show that normal brain development reconciles glioblastoma development, suggests a possible origin for glioblastoma hierarchy, and helps to identify cancer stem cell-specific targets.

癌症干细胞对于癌症的发生、发展和治疗耐药性至关重要。我们对这些过程以及它们与胶质母细胞瘤异质性的关系的理解是有限的。为了克服这些限制，我们对 53586 个成人胶质母细胞瘤细胞和 22637 个正常人胎儿脑细胞进行了单细胞 RNA 测序，并将发育中的人脑的谱系层次结构与癌细胞的转录组进行了比较。我们发现了一个以神经胶质祖细胞样为中心的保守的神经三系癌症层次结构。我们还发现该祖细胞群包含大多数癌症循环细胞，并且利用 RNA 速度，通常是其他细胞类型的起源。最后，我们表明该层次图可用于识别祖癌干细胞特异的治疗靶点。我们的分析表明，正常的大脑发育可以协调胶质母细胞瘤的发育，提示胶质母细胞瘤层次结构的可能起源，并有助于识别癌症干细胞特异性靶点。