Wnt activation as a therapeutic strategy in medulloblastoma

Branavan Manoranjan, Chitra Venugopal, David Bakhshinyan, Ashley A. Adile, Laura Richards, Michelle M. Kameda-Smith, Owen Whitley, Anna Dvorkin-Gheva, Minomi Subapanditha, Neil Savage, Nazanin Tatari, Dillon McKenna, Blessing Bassey-Archibong, Neil Winegarden, Robin Hallett, John P. Provias, Blake Yarascavitch, Olufemi Ajani, Adam Fleming, Gary D. Bader, Trevor J. Pugh, Bradley W. Doble and Sheila K. Singh ()
Additional contact information
Branavan Manoranjan: University of Calgary
Chitra Venugopal: McMaster University
David Bakhshinyan: McMaster University
Ashley A. Adile: McMaster University
Laura Richards: University Health Network
Michelle M. Kameda-Smith: McMaster University
Owen Whitley: University of Toronto
Anna Dvorkin-Gheva: McMaster University
Minomi Subapanditha: McMaster University
Neil Savage: McMaster University
Nazanin Tatari: McMaster University
Dillon McKenna: McMaster University
Blessing Bassey-Archibong: McMaster University
Neil Winegarden: University Health Network
Robin Hallett: Northern Biologics
John P. Provias: McMaster University
Blake Yarascavitch: McMaster University
Olufemi Ajani: McMaster University
Adam Fleming: McMaster University
Gary D. Bader: University of Toronto
Trevor J. Pugh: University Health Network
Bradley W. Doble: McMaster University
Sheila K. Singh: McMaster University

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB. With single cell RNA-seq technology, we demonstrate the presence of rare Wnt-active cells in non-Wnt MBs, which functionally retain the impaired tumorigenic potential of Wnt MB. In treating MB xenografts with a Wnt agonist, we provide a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MB and thereby support emerging data for a context-dependent tumor suppressive role for Wnt/β-catenin signaling.

Date: 2020
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DOI: 10.1038/s41467-020-17953-4

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