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Glioblastoma, Developing Brain Cell Populations Show Similarities in Single-Cell RNA-Seq Study

NEW YORK – A single-cell transcriptomics analysis has uncovered parallels between cellular populations present in glioblastoma (GBM) brain cancers and those found in developing human brains — part of a cellular "hierarchy" stemming from glial progenitor cells that may inform future treatment strategies.

"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," senior and corresponding author Kevin Petrecca, a neuroscientist at McGill University, and his colleagues wrote in a paper published in Nature Communications on Wednesday.

For their analyses, the researchers generated massively parallel scRNA-seq data on nearly 53,600 individual GBM tumors cells. They then compared and contrasted the transcriptional features found there with those of more than 23,600 single cells from normal developing fetal brain samples. The results suggested that GBM tumors contain cells that resemble those in the developing human brain, including fast-dividing progenitor cancer cells that spawn other tumor cell types.

It remains to be seen how the cancer cell populations identified in the study interact with the GBM microenvironment, Petrecca noted in a statement. Even so, he said, "this study serves as a good starting point to begin to understand how glioblastoma originates and evolves prior to treatments.

Cancer stem cells can contribute to the advent and treatment responses observed in GBM and other tumor types, the team explained, but there is still a ways to go when it comes to understanding the extent of the heterogeneity that exists within and across stem cells in GBM tumors and the contributions these cells might make to post-treatment disease recurrence.

To explore that possibility, the researchers performed 10x Genomics droplet-based scRNA-seq on 53,586 individual tumor cells or enriched glioblastoma stem cells from 16 patients afflicted with a GBM subtype lacking mutations in the IDH gene. In those samples, they saw clusters with transcriptional and copy number patterns that lined up with normal, tumor, or progenitor cell types, along with clues to the clonal populations present within each tumor.

Within the tumor and stem cell-like clusters, for example, gene expression patterns pointed to cells from lineages related to normal neural development — findings that the team looked into more closely by developing a "fetal brain roadmap" with scRNA-seq data for 22,637 cells that were isolated from the telencephalon brain region of four human fetuses at 13 to 21 weeks gestation and enriched for progenitor and neural stem cells.

Broadly speaking, the researchers identified gene expression signatures in the tumor cells that tracked with those found in glial progenitor, oligo-lineage, astrocyte, mesenchymal, and neuronal cells. They noted that "cycling," or cell division-prone cancer cells in the tumors tended to share gene expression signatures with glial progenitor cells, as did the apparent glioblastoma stem cells.

"By increasing the number of cells sequenced, and enriching for neural stem cells, we uncovered a cell type with a transcriptomic signature suggestive of a [glial progenitor cell]," the authors reported. "Additional work such as fate mapping will be necessary to uncover the exact position of these cells within the developmental hierarchy of the brain."

Based on the apparent treatment resistance and tumor proliferation features found in the progenitor cell population in subsequent patient-derived cell line and xenograft experiments, the team searched for potential treatment targets and responses in the context of glial stem cells.

"Together, these findings are relevant to cancer biology and therapeutics development," the authors wrote, adding that "rapidly cycling progenitor cancer cells are often at [the] apex of the cancer cell hierarchy and thus serve as a prime cell population to target."