Our understanding of glioblastoma heterogeneity, and the relevance of GSCs in this process, is limited. There are presently no treatments targeting GSCs. These data suggest that GSCs may have a role in cancer development and recurrence. Studies have shown that GSCs resist radiotherapy 6 and TMZ chemotherapy 18, 31. Although the GSC compartment is small in comparison with the differentiated compartment, it is relevant clinically. Importantly, stem cells isolated from different tumors show variability with respect to marker expression 28, 29, 30, suggesting that some degree of interpatient and/or intratumoral heterogeneity exists within the stem cell compartment as well. GSCs can propagate tumors from one host to another 14, and can expand and develop to form brain cancers in orthotopic xenograft models that recapitulate the tumor from which they were extracted 14, 27. Consistently, glioblastoma stem cells (GSCs) do possess these properties. The CSC theory is derived from our understanding of normal stem cells 15 and posits that such cells must exhibit properties of self-renewal and the ability to produce differentiated progeny. Although a neurodevelopmental bi-lineage hierarchy has been shown to explain a portion of this heterogeneity in IDH mutant glioma 24, 25 and high-grade pediatric glioma 26, this has not been possible in adult IDHwt glioblastoma.Īnother layer of complexity was uncovered by the discovery of a small subpopulation of glioblastoma cells that have stem-like properties 13, 14. This interpatient and intratumoral heterogeneity poses a daunting challenge for research programs aimed at developing targeted therapeutic approaches 23 and may explain the failures of such approaches in this disease. More recently, it has been shown that multiple subtypes coexist in different regions 21, 22 and different cells 12, 20 within the same tumor. Despite very different transcriptomic profiles and associated genomic alterations, no differences in survival exist between these subtypes. The more recent classification now excludes the neural subtype 20. Analysis of whole-tumor transcriptomic data extracted from predominantly differentiated cells showed that glioblastoma clustered into four main subtypes: proneural neural classical and mesenchymal 19. Interpatient heterogeneity was established through genomic and transcriptomic analyses by The Cancer Genome Atlas (TCGA) research network 11. The molecular and genomic heterogeneity, and the persistence of a subpopulation of cancer cells with stem-like properties following radiotherapy and chemotherapy, are believed to be the main causes of resistance to treatment and the associated extremely poor outcomes 6, 17, 18. This cancer is composed of two main cell compartments: a larger differentiated cell compartment that forms the basis of our understanding of the genomic and molecular underpinnings of the disease 11, 12 and a smaller, less well-characterized compartment of cells with stem-like capabilities 13, 14, 15, 16. Following radiotherapy and temozolomide (TMZ) chemotherapy, the median time to recurrence is 7 months, with patients succumbing to the disease 7 months thereafter 9, 10. IDH wild-type (IDHwt) glioblastoma, the most common adult primary brain cancer 8, exemplifies these obstacles. Significant obstacles hampering the development of effective cancer therapeutics include tumor heterogeneity 1, 2, 3, 4, 5, and the persistence of incompletely understood cancer stem cells (CSCs) that give rise to cancer recurrence 6, 7. 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. Finally, we show that this hierarchal map can be used to identify therapeutic targets specific to progenitor cancer stem 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. We find a conserved neural tri-lineage cancer hierarchy centered around glial progenitor-like cells. 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. Our understanding of these processes, and how they relate to glioblastoma heterogeneity, is limited. Cancer stem cells are critical for cancer initiation, development, and treatment resistance.
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