Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

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Summary:

The study of the origin and development of cerebellar tumors has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. We used single-cell transcriptomics to study >60,000 cells from the developing murine cerebellum, and show that different molecular subgroups of childhood cerebellar tumors mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. Sonic Hedgehog medulloblastoma transcriptionally mirrors the granule cell hierarchy as expected, whereas Group3 MB resemble Nestin ^+ve stem cells, Group 4 MB resemble unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the pre-natal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumors demonstrates that many bulk tumors contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumors as a disorder of early brain development, and provide a proximate explanation for the peak incidence of cerebellar tumors in early childhood.

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Prediction of central nervous system embryonal tumour outcome based on gene expression.

Scott Pomeroy, Pablo Tamayo, Michelle Gaasenbeek … (2002)

Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.

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Subtypes of medulloblastoma have distinct developmental origins

Paul Gibson, Yiai Tong, Giles Robinson … (2010)

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumor subtypes that together comprise the most common malignant childhood brain tumor1–4. These tumors are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) following aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH-subtype)3–8. The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here, we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT-subtype)1,3,4, arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumors infiltrate the dorsal brainstem, while SHH-subtype tumors are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem that included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice and in 15% of cases in which Tp53 was concurrently deleted, progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

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Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog.

R. J. Wechsler-Reya, M P Scott (1999)

Cerebellar granule cells are the most abundant type of neuron in the brain, but the molecular mechanisms that control their generation are incompletely understood. We show that Sonic hedgehog (Shh), which is made by Purkinje cells, regulates the division of granule cell precursors (GCPs). Treatment of GCPs with Shh prevents differentiation and induces a potent, long-lasting proliferative response. This response can be inhibited by basic fibroblast growth factor or by activation of protein kinase A. Blocking Shh function in vivo dramatically reduces GCP proliferation. These findings provide insight into the mechanisms of normal growth and tumorigenesis in the cerebellum.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 25 March 2019

Publication date (Electronic): 01 May 2019

Publication date (Print): August 2019

Publication date PMC-release: 01 November 2019

Volume: 572

Issue: 7767

Pages: 67-73

Affiliations

[1 ]Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada

[2 ]The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada

[3 ]Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

[4 ]Computational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada

[5 ]Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

[6 ]Division of Haematology / Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

[7 ]Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

[8 ]Brain Tumor Program, Children’s Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States

[9 ]Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

[10 ]Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, Canada

[11 ]Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada

[12 ]Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

[13 ]Department of Surgery, McMaster University, Hamilton, Ontario, Canada

[14 ]Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada

[15 ]Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada

[16 ]Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

[17 ]Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada

[18 ]Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

[19 ]Ontario Institute for Cancer Research, Toronto, Ontario, Canada

[20 ]Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States

[21 ]Department of Human Genetics, McGill University, Montreal, Quebec, Canada

[22 ]Lady Davis Research Institute, Jewish General Hospital, Montreal, Quebec, Canada

[23 ]Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States

[24 ]Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada

[25 ]Department of Surgery and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

Author notes

[*]

These authors contributed equally to this work

[#]

These authors jointly supervised this work

Author contribution:

M.C.V.,I.E.H.,L.K.D. designed, performed and analysed the majority of the experiments in this study. H.F. contributed to the pre-processing of scRNA-seq sequencing data. B.L.H. contributed to timed mating and tissue isolation in developing mouse embryos. Y.S. and L.H. contributed to the SNV and CNV analysis of the scRNA-seq data. V.R. contributed to the clinical analysis of the primary tumor samples. L.D.H contributed to the differential gene expression analysis. S.K. contributed to tissue helped with tissue isolation, preparation and statistical analysis of scRNA-seq data. V.F. contributed to literature review, marker gene discovery and cell cluster annotations. P.S.,H.S.,A.S.M.,F.M.G. contributed to the analysis of the bulk RNA-seq data and the data availability submission. J.J.L., K.J., D.P.,A.M.,B.L.,M.A.Q. contributed to the collection and processing of primary tumor samples. K.N. optimized the 10X Genomics scRNA-seq protocols. C.D., X.W, F.N. provided reagents, equipment and expert advice. S.C.M.,L.G., S.K.S.,J.A.C.,M.A.M.,D.M.,P.D.,T.P.,F.N.,E.M.T.,C.L.K. provided clinical samples and helped design the study. A.L.J provided expert advice on identification of developing cerebellar cell populations. N.J., L.S. and M.D.T. supervised the project and wrote the manuscript.

Author information: For correspondence please contact Lincoln Stein ( lincoln.stein@ 123456oicr.on.ca ), Nada Jabado ( nada.jabado@ 123456mcgill.ca ) or Michael D Taylor ( mdt.cns@ 123456gmail.com ).

Article

Manuscript ID: NIHMS1525286

DOI: 10.1038/s41586-019-1158-7

PMC ID: 6675628

PubMed ID: 31043743

SO-VID: 441f44da-c8ea-4a77-91c6-92da977ddf22

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Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

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Annual Reviews Child Development

Most cited references 27

Prediction of central nervous system embryonal tumour outcome based on gene expression.

Subtypes of medulloblastoma have distinct developmental origins

Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog.

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