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

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, Wnt lo 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.

Ameloblastomas Exhibit Stem Cell Potential, Possess Neurotrophic Properties, and Establish Connections with Trigeminal Neurons

“…Notch signaling is a fundamental player in the establishment of stem cell fate and behavior in development, regeneration and disease [12][13][14]49]. Notch signaling was shown to be necessary for the maintenance of cancer stem cells in different types of tumors [18,[50][51][52]. As such, it is the target of numerous therapeutic antineoplastic approaches [15,18,53].…”

Targeting cancer stem cell pathways for cancer therapy

“…10 The Notch signaling pathway plays an important role in the maintenance of CSCs 565,566 and can induce CSC differentiation. Abnormal activity of the Notch signaling pathway has been observed in many cancers, such as leukemia, 567 glioblastoma, 568,569 breast cancer, 570 lung cancer, 571 ovarian cancer, 572 pancreatic cancer, 573 and colon cancer. 574 At present, there are three major clinical methods used to inhibit Notch signaling, secretase inhibition (γ-secretase inhibitor (GSI)), Notch receptor or ligand antibodies, and combination therapy with other pathways.…”

A novel molecular link between HOXA9 and WNT6 in glioblastoma identifies a subgroup of patients with particular poor prognosis

“…), suggesting WNT6 and the WNT/β‐catenin signaling pathway as effectors of HOXA9‐mediated aggressiveness in GBM (Costa et al , ; Pojo et al , ). Interestingly, it was recently reported that HOXA genes are part of a gene‐signature characteristic of WNT‐dependent glioma stem cells (Rajakulendran et al , ), which fits well with our data linking HOXA9 and WNT6 in GBM. This link is particularly relevant from a clinical perspective, as it may reveal novel therapeutic opportunities targeting WNT signaling to revert the malignant behaviors of highly aggressive WNT6‐high and HOXA9‐high GBMs, all of which present particularly poor clinical outcome.…”