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; Sheila K Singh

doi:10.1038/s41467-020-17953-4

Wnt activation as a therapeutic strategy in medulloblastoma

Nat Commun. 2020 Aug 28;11(1):4323. doi: 10.1038/s41467-020-17953-4.

Authors

Branavan Manoranjan^{1

2

3}, Chitra Venugopal^{2

4}, David Bakhshinyan^{2

3}, Ashley A Adile^{2

3}, Laura Richards^{5

6}, Michelle M Kameda-Smith^{2

3}, Owen Whitley^{7

8}, Anna Dvorkin-Gheva⁹, Minomi Subapanditha², Neil Savage², Nazanin Tatari², Dillon McKenna^{2

4}, Blessing Bassey-Archibong², Neil Winegarden^{5

6}, Robin Hallett¹⁰, John P Provias⁹, Blake Yarascavitch⁴, Olufemi Ajani⁴, Adam Fleming¹¹, Gary D Bader^{7

8

12}, Trevor J Pugh^{5

6}, Bradley W Doble^{2

3

13

14}, Sheila K Singh^{15

16

17}

Affiliations

¹ Section of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, AB, T2N 1N4, Canada.
² McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada.
³ Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, L8N 3Z5, Canada.
⁴ Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, L8N 3Z5, Canada.
⁵ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 2M9, Canada.
⁶ Department of Medical Biophysics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁸ Department of Computer Science, University of Toronto, Toronto, ON, M5S 1A8, Canada.
⁹ Department of Pathology, Faculty of Health Sciences, McMaster University, Hamilton, ON, L8N 3Z5, Canada.
¹⁰ Northern Biologics, Toronto, ON, M5G 1L7, Canada.
¹¹ Department of Pediatrics, Faculty of Health Sciences, McMaster University, Hamilton, ON, L8N 3Z5, Canada.
¹² The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada.
¹³ Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, R3E 0W2, Canada.
¹⁴ Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, R3E 0W2, Canada.
¹⁵ McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4K1, Canada. ssingh@mcmaster.ca.
¹⁶ Department of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, L8N 3Z5, Canada. ssingh@mcmaster.ca.
¹⁷ Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, L8N 3Z5, Canada. ssingh@mcmaster.ca.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms / pathology
Cerebellar Neoplasms / therapy*
Disease Models, Animal
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Heterografts
Humans
Medulloblastoma / genetics
Medulloblastoma / pathology
Medulloblastoma / therapy*
Mice
Stem Cells
Wnt Proteins / genetics
Wnt Proteins / pharmacology*
Wnt Proteins / therapeutic use*
Wnt Signaling Pathway
beta Catenin / therapeutic use

Substances

Wnt Proteins
beta Catenin

Grants and funding

CIHR/Canada