1. Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells.
- Author
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Rajakulendran N, Rowland KJ, Selvadurai HJ, Ahmadi M, Park NI, Naumenko S, Dolma S, Ward RJ, So M, Lee L, MacLeod G, Pasiliao C, Brandon C, Clarke ID, Cusimano MD, Bernstein M, Batada N, Angers S, and Dirks PB
- Subjects
- Cell Line, Tumor, Cell Self Renewal genetics, Gene Expression Regulation, Neoplastic genetics, Glioblastoma physiopathology, Humans, Receptors, Notch genetics, Receptors, Notch metabolism, Wnt Proteins genetics, Wnt Proteins metabolism, Cell Differentiation genetics, Neoplastic Stem Cells cytology, Signal Transduction
- 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, Wnt
hi 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., (© 2019 Rajakulendran et al.; Published by Cold Spring Harbor Laboratory Press.)- Published
- 2019
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