Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells

  1. Peter B. Dirks2,3,9,10
  1. 1Leslie Dan Faculty of Pharmacy, Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada;
  2. 2Developmental and Stem Cell Biology Program, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada;
  3. 3Faculty of Medicine, Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 0A4, Canada;
  4. 4Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada;
  5. 5St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada;
  6. 6Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada;
  7. 7Institute of Genetics and Molecular Medicine, Edinburgh EH4 2XU, United Kingdom;
  8. 8Faculty of Medicine, Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
  9. 9Faculty of Medicine, Department of Surgery, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
  10. 10Division of Neurosurgery The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
  1. Corresponding authors: stephane.angers{at}utoronto.ca, peter.dirks{at}sickkids.ca

  1. ↵12 These authors contributed equally to this work.

  • ↵11 Present address: OCAD University, Toronto, Ontario M5T 1W1, Canada.

Abstract

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/βcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnthi GBM cells (which exhibit high levels of βcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wntlo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/βcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.

Keywords

Footnotes

  • Received October 22, 2018.
  • Accepted February 19, 2019.

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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This Article

  1. Published in Advance March 6, 2019, doi: 10.1101/gad.321968.118 Genes & Dev. 33: 498-510 © 2019 Rajakulendran et al.; Published by Cold Spring Harbor Laboratory Press

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ORCID

  1. Profile for Angers, S.http://orcid.org/0000-0001-7241-9044

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