Childhood cerebellar tumours mirror conserved fetal transcriptional programs

• Published in: Nature (London) Vol. 572; no. 7767; pp. 67 - 73
• Main Authors: Vladoiu, Maria C., El-Hamamy, Ibrahim, Donovan, Laura K., Farooq, Hamza, Holgado, Borja L., Sundaravadanam, Yogi, Ramaswamy, Vijay, Hendrikse, Liam D., Kumar, Sachin, Mack, Stephen C., Lee, John J. Y., Fong, Vernon, Juraschka, Kyle, Przelicki, David, Michealraj, Antony, Skowron, Patryk, Luu, Betty, Suzuki, Hiromichi, Morrissy, A. Sorana, Cavalli, Florence M. G., Garzia, Livia, Daniels, Craig, Wu, Xiaochong, Qazi, Maleeha A., Singh, Sheila K., Chan, Jennifer A., Marra, Marco A., Malkin, David, Dirks, Peter, Heisler, Lawrence, Pugh, Trevor, Ng, Karen, Notta, Faiyaz, Thompson, Eric M., Kleinman, Claudia L., Joyner, Alexandra L., Jabado, Nada, Stein, Lincoln, Taylor, Michael D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2019; Nature Publishing Group
• Subjects: 38/39; 38/91; 631/67; 631/67/1922; Analysis; Animals; Astrocytoma; Brain; Brain cancer; Brain tumors; Cell cycle; Cell differentiation; Cerebellar Neoplasms - classification; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - pathology; Cerebellum; Cerebellum - cytology; Cerebellum - embryology; Cerebellum - metabolism; Child; Children; Evolution, Molecular; Female; Fetus - cytology; Fetus - metabolism; Fetuses; Gene expression; Gene Expression Regulation, Developmental; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic transcription; Genomes; Glioma - classification; Glioma - genetics; Glioma - pathology; Heterogeneity; Humanities and Social Sciences; Humans; Medulloblastoma; Medulloblastoma - classification; Medulloblastoma - genetics; Medulloblastoma - pathology; Methods; Mice; multidisciplinary; Nervous system; Nestin; Neurodevelopmental disorders; Progenitor cells; Science; Science (multidisciplinary); Sequence Analysis, RNA; Single-Cell Analysis; Sonic hedgehog; Stem cell transplantation; Stem cells; Subgroups; Time Factors; Transcription; Transcription, Genetic; Transcriptome - genetics; Tumors; Tumors in children; Unipolar brush cells; Canada
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1158-7

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin + stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood. Sequencing data from the developing cerebellum are compared with bulk sequencing data from paediatric tumours, providing insights into their potential origins and suggesting that many cerebellar tumours have their origins early in utero.