Medulloblastoma Arises from the Persistence of a Rare and Transient Sox2 + Granule Neuron Precursor.

Autor:	Selvadurai HJ; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Luis E; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Desai K; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Lan X; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Vladoiu MC; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 0A4, Canada., Whitley O; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; The Donnelly Centre, University of Toronto, ON M5T 1W1, Canada., Galvin C; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Vanner RJ; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Lee L; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Whetstone H; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Kushida M; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Nowakowski T; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA., Diamandis P; Department of Pathology, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; Division of Pathology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Hawkins C; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Pathology, Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada; Division of Pathology, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada., Bader G; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; The Donnelly Centre, University of Toronto, ON M5T 1W1, Canada., Kriegstein A; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA., Taylor MD; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 0A4, Canada; Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada., Dirks PB; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Neurosurgery, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: peter.dirks@sickkids.ca.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2020 Apr 14; Vol. 31 (2), pp. 107511.
DOI:	10.1016/j.celrep.2020.03.075
Abstrakt:	Medulloblastoma (MB) is a neoplasm linked to dysregulated cerebellar development. Previously, we demonstrated that the Sonic Hedgehog (SHH) subgroup grows hierarchically, with Sox2 + cells at the apex of tumor progression and relapse. To test whether this mechanism is rooted in a normal developmental process, we studied the role of Sox2 in cerebellar development. We find that the external germinal layer (EGL) is derived from embryonic Sox2 + precursors and that the EGL maintains a rare fraction of Sox2 + cells during the first postnatal week. Through lineage tracing and single-cell analysis, we demonstrate that these Sox2 + cells are within the Atoh1 + lineage, contribute extensively to adult granule neurons, and resemble Sox2 + tumor cells. Critically, constitutive activation of the SHH pathway leads to their aberrant persistence in the EGL and rapid tumor onset. We propose that failure to eliminate this rare but potent developmental population is the tumor initiation mechanism in SHH-subgroup MB. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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