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Medulloblastoma Molecular Studies Point to Cell Origins, Progenitor Differentiation

NEW YORK – A pair of new studies suggest that a subset of medulloblastoma (MB) brain tumors that develop in childhood may be a consequence of molecular alterations that prompt progenitor cell shifts during brain development.

Past studies have linked Sonic hedgehog (SHH) signaling pathway mutations to the SHH MB subgroup of tumors, originating in the upper rhombic lip granule cell lineage, while altered WNT signaling activity has been implicated in WNT MB tumors in the lower rhombic lip, the study authors explained. However, the group 3 (G3) and group 4 (G4) subgroups have been less completely characterized.

"G4 MB is proposed to arise in the unipolar brush cell (UBC) lineage, whereas G3 MB appears to arise from an earlier population of stem cells," co-senior and corresponding author Michael Taylor, a pediatric neurosurgeon and researcher affiliated with the Hospital for Sick Children (SickKids) and the University of Toronto, and his colleagues wrote in Nature on Wednesday. "Activation of MYC is seen in many G3 tumors; however, the convergence and/or significance of low-incidence driver mutations in G4 MB remains unclear."

To better understand these MB subgroups, researchers at SickKids, the University of Manitoba's Max Rady College of Medicine, Japan's National Cancer Center in Tokyo, the Seattle Children's Research Institute, and other centers performed transcriptome sequencing on 545 of the G4 and G3 MB tumor samples, searching for recurrently altered genes and pathways.

In particular, the researchers flagged epigenetic modifier and cell cycle genes with frequent mutations in the MB subtypes considered, along with genes in the ELP, FANC, and CHD families and components of the "core binding factor alpha" (CBFA) polyprotein complex.

Within the G4 MB tumors, in particular, the team tracked down recurrent changes in the histone methyltransferase-coding gene PRDM6, the histone demethylase-coding genes KDM6 and KDM2B, several transcriptional co-repressor genes, and other CBFA complex contributors.

The authors noted that G4 MB tumor cells were transcriptionally similar to CBFA family gene-expressing UBC progenitor cells population in the rhombic lip during human cerebellar development — results shored up with single-nucleus RNA sequencing profiles generated for developing cerebellum cells and cells isolated from 18 G3, G4, or SHH subtype tumors.

"The specific nature of the split human [rhombic lip], which is destined to generate most of the neurons in the human brain and its high level of susceptible … progenitor cells probably predisposes our species to the development of G4 MB," they suggested.

Together, the researchers reported, their results suggested that CBFA complex-inhibiting medulloblastoma mutations identified in G3 and G4 subtype tumors lead to stalled progenitor cell differentiation in the brain's cerebellar rhombic lip subventricular zone during development, leaving behind pre-malignant cells that can progress to MB tumors in childhood.

The results prompted speculation that there may be ways of preventing such progenitor cell stalling and pre-malignant cell formation — a hypothesis supported by gene knockdown small inhibiting RNA experiments used to dial down levels of the CBFA complex gene OTX2 in "tumorsphere" models developed from MYC-amplified G3 MB cell lines and subsequent single-nucleus RNA sequencing analyses.

"We wanted to see how we could speed up the development of more effective therapies, but what we discovered may be even better than what we imagined," SickKids' Taylor said in a statement. "Preventing cancer from happening in the first place instead of treating it after it happens is the best possible outcome for children."

For a related Nature study, researchers at St. Jude Children's Research Hospital, Seattle Children's Research Institute, and other centers in the US and the UK shared findings from multiomic analyses focused on finding the cellular origins of different MB subtypes, particularly MB tumors in the SHH, G3, and G4 subtypes.

Based on single-cell or single-nucleus RNA-seq data for more than 52,400 developing human fetal cerebellum cells — combined with tumor RNA-seq, results from subsequent CRISPR-based gene editing experiments, and other data — the team highlighted photoreceptor- and unipolar brush cell-related signatures from the rhombic lip lineage in the G3 and G4 forms of MB.

"Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development," authors of that study explained, noting that G3 and G4 tumors "are defined by the extent of their differentiation" within the glutamatergic cerebellar nuclear neuron/UBC lineage progenitor trajectory.

They argued that the work "emphasizes the importance of examining the origins of childhood cancer in human developmental contexts, and will serve as a methodological framework for resolving the origins of other pediatric and adult malignancies."

In a Nature commentary article accompanying the studies, the University of Cincinnati's Timothy Phoenix, who was not involved in the research, noted that new findings by the two teams offered a refined look at G3 and G4 MB tumor origins.

"Every villain has an origin story, and medulloblastoma is no exception," Phoenix concluded. "Let's hope that these developments will lead to heroic success in providing clinical benefits."

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