Resolving medulloblastoma cellular architecture by single-cell genomics

Volker Hovestadt, Kyle S. Smith, Laure Bihannic, Mariella G. Filbin, McKenzie K.L. Shaw, Alicia Baumgartner, John C. DeWitt, Andrew Groves, Lisa Mayr, Hannah R. Weisman, Alyssa R. Richman, Marni E. Shore, Liliana Goumnerova, Celeste Rosencrance, Robert A. Carter, Timothy N. Phoenix, Jennifer L. Hadley, Yiai Tong, Jim Houston, Richard A. AshmunMichael DeCuypere, Tanvi Sharma, Diane Flasch, Antonina Silkov, Keith L. Ligon, Scott L. Pomeroy, Miguel N. Rivera, Orit Rozenblatt-Rosen, Jessica M. Rusert, Robert J. Wechsler-Reya, Xiao Nan Li, Andreas Peyrl, Johannes Gojo, Dominik Kirchhofer, Daniela Lötsch, Thomas Czech, Christian Dorfer, Christine Haberler, Rene Geyeregger, Angela Halfmann, Charles Gawad, John Easton, Stefan M. Pfister, Aviv Regev, Amar Gajjar, Brent A. Orr, Irene Slavc, Giles W. Robinson, Bradley E. Bernstein*, Mario L. Suvà, Paul A. Northcott

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.

Original languageEnglish (US)
Pages (from-to)74-79
Number of pages6
JournalNature
Volume572
Issue number7767
DOIs
StatePublished - Aug 1 2019

ASJC Scopus subject areas

  • General

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