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Nature. 2019 Aug;572(7767):74-79. doi: 10.1038/s41586-019-1434-6. Epub 2019 Jul 24.

Resolving medulloblastoma cellular architecture by single-cell genomics.

Author information

1
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
2
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
3
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA.
4
Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
5
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
6
Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
7
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
8
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN, USA.
9
Department of Flow Cytometry, St Jude Children's Research Hospital, Memphis, TN, USA.
10
Department of Surgery, St Jude Children's Research Hospital, Memphis, TN, USA.
11
Hopp Children's Cancer Centre at National Centre for Tumour Diseases Heidelberg (KiTZ), Heidelberg, Germany.
12
Division of Paediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
13
Department of Oncologic Pathology, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA, USA.
14
Department of Neurology, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.
15
Klarman Cell Observatory (KCO), Broad Institute of Harvard and MIT, Cambridge, MA, USA.
16
Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA.
17
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Research Discovery Institute, La Jolla, CA, USA.
18
Texas Children's Cancer Centre, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
19
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
20
Department of Neurosurgery, Medical University of Vienna, Vienna, Austria.
21
Institute of Neurology, Medical University of Vienna, Vienna, Austria.
22
Clinical Cell Biology, Children's Cancer Research Institute (CCRI), St Anna Kinderkrebsforschung, Vienna, Austria.
23
Department of Paediatric Haematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany.
24
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
25
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bernstein.bradley@mgh.harvard.edu.
26
Broad Institute of Harvard and MIT, Cambridge, MA, USA. bernstein.bradley@mgh.harvard.edu.
27
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. suva.mario@mgh.harvard.edu.
28
Broad Institute of Harvard and MIT, Cambridge, MA, USA. suva.mario@mgh.harvard.edu.
29
Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN, USA. paul.northcott@stjude.org.

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.

PMID:
31341285
DOI:
10.1038/s41586-019-1434-6

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