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Medulloblastoma Molecular Subtypes Refined With Single-Cell Transcriptome Data

NEW YORK – Findings from a single-cell RNA sequencing (scRNA-seq) study of medulloblastoma have provided a clearer picture of the molecular subgroups that exist for the malignant childhood tumor, along with the roots of such tumors and the heterogeneity found within and between them.

"[O]ur work provides a cellular atlas of [medulloblastoma] across all subgroups and a cross-species comparison of cerebellar development, highlighting putative subgroup-specific origins," corresponding authors Mario Suva and Bradley Bernstein of Massachusetts General Hospital and the Broad Institute and Paul Northcott of St. Jude Children's Research Hospital and their colleagues wrote.

They noted that the analyses "also define the cellular states underlying each MB subgroup, disentangling determinants of intra- and intertumoral heterogeneity."

As they reported online today in Nature, the researchers sequenced the transcriptome of more than 8,700 individual cells from 25 medulloblastoma tumors. Together with genome sequence, exome sequence, or methylation profiles for the tumors —  as well as patient-derived xenograft profiles and gene expression data from mouse cerebellum samples taken across more than a dozen developmental stages — the gains, losses, and other expression clues gleaned from the scRNA-seq data made it possible to characterize the WNT, SHH, Group 3, and Group 4 subtypes of medulloblastoma within the context of normal brain cell development.

While the Group 4 tumors were typically made up of differentiated neuronal-like neoplastic cells, the team found that tumors from the remaining molecular subtypes contained undifferentiated and differentiated malignant cells from neuronal-like cells that varied from one subtype to the next.

In the case of SHH tumors, for example, the extent of tumor cell differentiation often varied with a patient's age, and cells shared features with granule neurons. Tumors from both Group 3 and Group 4 subtypes also shared features with developing brain cells spanning primitive progenitor-like cells to cells resembling more mature neuronal cells.

By folding in expression features found in the developing mouse cerebellum, meanwhile, the researchers got a glimpse at some of the possible cells of origin behind specific human medulloblastoma cell subtypes.

Based on tumor genotype, gene expression, and diagnostic patterns analyzed in past studies, the authors explained, it has been suspected that each of the medulloblastoma subtypes represents a distinct cell type that has taken a cancerous turn at a specific time and place during brain development.

"Despite extensive characterization of [medulloblastoma] genomic landscapes," they wrote, "effective subgroup-specific therapies have yet to emerge, suggesting that a deeper understanding of the biological and cellular basis of [medulloblastoma] is essential."

For the new analyses — designed to complement studies previously performed with bulk medulloblastoma tumor samples — the researchers used the Smart-seq2 protocol to conduct single-cell RNA-seq on 8,734 cells from 25 prospectively collected medulloblastoma samples, including 23 samples collected at the time of diagnosis and two more from recurrent tumors.

To that, the team added whole-genome sequence data for five of the medulloblastoma cases, exome sequencing for 12 of the tumors, and array-based methylation profiles for each of the tumor samples. It also established 11 patient-derived xenografts to delve further into medulloblastoma subtypes after growth in the cerebellum of mouse models and used 10x Genomics technology to assess some 80,000 cells from the developing mouse cerebellum.

"Collectively, these data provide insights into the molecular and cellular architecture of [medulloblastoma] across all subgroups, with the potential to inform future studies aimed at improving patient outcomes," the authors wrote, noting that results from the current analyses "will enable future studies to assess translational opportunities and to evaluate the impact of therapeutic approaches on the spectrum of cellular states that drive [medulloblastoma]."