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

Hayden J Selvadurai; Erika Luis; Kinjal Desai; Xiaoyang Lan; Maria C Vladoiu; Owen Whitley; Ciaran Galvin; Robert J Vanner; Lilian Lee; Heather Whetstone; Michelle Kushida; Tomasz Nowakowski; Phedias Diamandis; Cynthia Hawkins; Gary Bader; Arnold Kriegstein; Michael D Taylor; Peter B Dirks

doi:10.1016/j.celrep.2020.03.075

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

Cell Rep. 2020 Apr 14;31(2):107511. doi: 10.1016/j.celrep.2020.03.075.

Authors

Hayden J Selvadurai¹, Erika Luis², Kinjal Desai¹, Xiaoyang Lan¹, Maria C Vladoiu³, Owen Whitley⁴, Ciaran Galvin¹, Robert J Vanner², Lilian Lee¹, Heather Whetstone¹, Michelle Kushida¹, Tomasz Nowakowski⁵, Phedias Diamandis⁶, Cynthia Hawkins⁷, Gary Bader⁴, Arnold Kriegstein⁵, Michael D Taylor⁸, Peter B Dirks⁹

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; The Donnelly Centre, University of Toronto, ON M5T 1W1, Canada.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.

PMID: 32294450
DOI: 10.1016/j.celrep.2020.03.075

Abstract

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.

Keywords: Sox2; cancer initiation; cancer stem cell; cerebellum development; lineage tracing; medulloblastoma; neural stem cell; single-cell RNA sequencing; sonic hedgehog.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Lineage / genetics
Cells, Cultured
Cerebellar Neoplasms / pathology
Cerebellum / embryology
Female
Hedgehog Proteins / metabolism
Humans
Male
Medulloblastoma / etiology*
Medulloblastoma / metabolism*
Mice, Knockout
Mice, Transgenic
Neoplasm Recurrence, Local / pathology
Neural Stem Cells / metabolism
Neurogenesis
Neurons / metabolism
SOXB1 Transcription Factors / metabolism*
SOXB1 Transcription Factors / physiology
Signal Transduction / physiology
Single-Cell Analysis / methods

Substances

Hedgehog Proteins
SOX2 protein, human
SOXB1 Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding