Resolving medulloblastoma cellular architecture by single-cell genomics

Volker Hovestadt, Kyle S. Smith, Laure Bihannic, Mariella G. Filbin, McKenzie 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. Ashmun, Michael 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 () and Paul A. Northcott ()
Additional contact information
Volker Hovestadt: Massachusetts General Hospital and Harvard Medical School
Kyle S. Smith: St Jude Children’s Research Hospital
Laure Bihannic: St Jude Children’s Research Hospital
Mariella G. Filbin: Massachusetts General Hospital and Harvard Medical School
McKenzie L. Shaw: Massachusetts General Hospital and Harvard Medical School
Alicia Baumgartner: Massachusetts General Hospital and Harvard Medical School
John C. DeWitt: Massachusetts General Hospital and Harvard Medical School
Andrew Groves: Dana-Farber Boston Children’s Cancer and Blood Disorders Center
Lisa Mayr: Medical University of Vienna
Hannah R. Weisman: Massachusetts General Hospital and Harvard Medical School
Alyssa R. Richman: Massachusetts General Hospital and Harvard Medical School
Marni E. Shore: Massachusetts General Hospital and Harvard Medical School
Liliana Goumnerova: Dana-Farber Boston Children’s Cancer and Blood Disorders Center
Celeste Rosencrance: St Jude Children’s Research Hospital
Robert A. Carter: St Jude Children’s Research Hospital
Timothy N. Phoenix: St Jude Children’s Research Hospital
Jennifer L. Hadley: St Jude Children’s Research Hospital
Yiai Tong: St Jude Children’s Research Hospital
Jim Houston: St Jude Children’s Research Hospital
Richard A. Ashmun: St Jude Children’s Research Hospital
Michael DeCuypere: St Jude Children’s Research Hospital
Tanvi Sharma: Hopp Children’s Cancer Centre at National Centre for Tumour Diseases Heidelberg (KiTZ)
Diane Flasch: St Jude Children’s Research Hospital
Antonina Silkov: St Jude Children’s Research Hospital
Keith L. Ligon: Broad Institute of Harvard and MIT
Scott L. Pomeroy: Boston Children’s Hospital
Miguel N. Rivera: Massachusetts General Hospital and Harvard Medical School
Orit Rozenblatt-Rosen: Broad Institute of Harvard and MIT
Jessica M. Rusert: NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Research Discovery Institute
Robert J. Wechsler-Reya: NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Research Discovery Institute
Xiao-Nan Li: Texas Children’s Hospital, Baylor College of Medicine
Andreas Peyrl: Medical University of Vienna
Johannes Gojo: Medical University of Vienna
Dominik Kirchhofer: Medical University of Vienna
Daniela Lötsch: Medical University of Vienna
Thomas Czech: Medical University of Vienna
Christian Dorfer: Medical University of Vienna
Christine Haberler: Medical University of Vienna
Rene Geyeregger: Medical University of Vienna
Angela Halfmann: St Anna Kinderkrebsforschung
Charles Gawad: St Jude Children’s Research Hospital
John Easton: St Jude Children’s Research Hospital
Stefan M. Pfister: Hopp Children’s Cancer Centre at National Centre for Tumour Diseases Heidelberg (KiTZ)
Aviv Regev: Broad Institute of Harvard and MIT
Amar Gajjar: St Jude Children’s Research Hospital
Brent A. Orr: St Jude Children’s Research Hospital
Irene Slavc: Medical University of Vienna
Giles W. Robinson: St Jude Children’s Research Hospital
Bradley E. Bernstein: Massachusetts General Hospital and Harvard Medical School
Mario L. Suvà: Massachusetts General Hospital and Harvard Medical School
Paul A. Northcott: St Jude Children’s Research Hospital

Nature, 2019, vol. 572, issue 7767, 74-79

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1434-6

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