Wnt activation as a therapeutic strategy in medulloblastoma
Branavan Manoranjan, Chitra Venugopal, David Bakhshinyan, Ashley Adile, Laura M. Richards, Michelle Kameda-Smith, Owen Whitley, Anna Dvorkin‐Gheva, Minomi Subapanditha, Neil Savage, Nazanin Tatari, Dillon McKenna, Blessing Bassey‐Archibong, Neil Winegarden, Robin Hallett, John Provias, Blake Yarascavitch, Olufemi Ajani, Adam Fleming, Gary D. Bader, Trevor J. Pugh, Bradley W. Doble, Sheila K. Singh
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.