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Medulloblastoma Single-Cell Study Yields Tumor-Initiating Cell Population Containing Outcome Clues

NEW YORK – Starting with single-cell sequencing on mouse tumor models of medulloblastoma, researchers from Cincinnati Children's Hospital Medical Center and elsewhere found a subset of glial progenitor cells that proliferate during tumor development and at tumor recurrence — expressing a gene that seems to coincide with poor outcomes in humans with the pediatric brain tumor.

Using 10x Genomics' droplet-based single-cell RNA sequencing, the team tallied transcriptome profiles in cells from mouse models of a medulloblastoma molecular subtype called Sonic Hedgehog medulloblastoma (SHH-MB). By analyzing the transcriptomes of individual medulloblastoma cells across of tumor development, the group saw a tumor-initiating role for a glial progenitor cells that express the OLIG2 gene.

When they dug into the cellular dynamics in the tumors — not only in mice, but also using single-cell RNA-seq profiles and other data generated for past studies of SHH-MB patients — the researchers saw that the OLIG2-expressing (OLIG2+) progenitor cells contribute to tumorigenesis, but remain largely dormant and stem-like in full-fledged medulloblastoma tumors. In recurrent or resistant tumors, on the other hand, their results suggest that the OLIG2+ progenitor cells are again enriched.

"That OLIG2+ glial progenitor cells are critical tumor-initiating cells might have important implications for the design of therapies to target cell lineage vulnerability during [medulloblastoma] tumorigenesis and recurrence," senior and co-corresponding author Richard Lu, an experimental hematology and cancer biology researcher at Cincinnati Children's Hospital, and his colleagues wrote in their study, published online today in Cancer Cell.

In the SHH-MB subtype — but not in the other three medulloblastoma subgroups — the team's analyses revealed an apparent relationship between enhanced OLIG2 expression and poorer-than-usual patient survival.

The researchers prompted SHH-MB formation in mouse models by tinkering with neural progenitor cells from early post-natal mice, knocking out Ptch, before doing 10x Genomics single-cell RNA-seq on dissociated mouse cerebellar cells collected over time. Transcriptomes in these cells clustered in nine groups, coinciding with a range of immune and brain cell types.

By following the development of different cell types in the tumors over time, they got a look at the rising and waning activity of stem-related genes in these cells over time, including glial progenitor cells with high OLIG2 expression.

"[W]e demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog medulloblastomas," the authors reported, "and identified OLIG2-expressing glial progenitors as transit-amplifying cells at tumor onset."

The team was able to stall or delay tumor progression in mice by knocking out the gene or experimentally dialing down its expression. Follow-up experiments hinted that the gene's tumorigenesis-boosting abilities come down to its interactions with chromatin and genes from cancer-promoting networks marked by AURORA-A/MYCN and other genes.

"The functional role of OLIG2 as an activator of oncogenic signaling as well as a vehicle for tumor recurrence suggests that targeting OLIG2 and downstream pathways might minimize the onset of therapeutic resistance and improve the outcomes of patients with SHH-MB," the authors concluded.