title: Wnt activation promotes neuronal differentiation of glioblastoma.
abstract: One of the biggest challenges in tumour research is the possibility to reprogram cancer cells towards less aggressive phenotypes. In this study, we reprogrammed primary Glioblastoma multiforme (GBM)-derived cells towards a more differentiated and less oncogenic phenotype by activating the Wnt pathway in a hypoxic microenvironment. Hypoxia usually correlates with malignant behaviours in cancer cells, but it has been recently involved, together with Wnt signalling, in the differentiation of embryonic and neural stem cells. Here, we demonstrate that treatment with Wnt ligands, or overexpression of β-catenin, mediate neuronal differentiation and halt proliferation in primary GBM cells. An hypoxic environment cooperates with Wnt-induced differentiation, in line with our finding that hypoxia inducible factor-1α (HIF-1α) is instrumental and required to sustain the expression of β-catenin transcriptional partners TCF-1 and LEF-1. In addition, we also found that Wnt-induced GBM cell differentiation inhibits Notch signalling, and thus gain of Wnt and loss of Notch cooperate in the activation of a pro-neuronal differentiation program. Intriguingly, the GBM sub-population enriched of cancer stem cells (CD133(+) fraction) is the primary target of the pro-differentiating effects mediated by the crosstalk between HIF-1α, Wnt, and Notch signalling. By using zebrafish transgenics and mutants as model systems to visualize and manipulate in vivo the Wnt pathway, we confirm that Wnt pathway activation is able to promote neuronal differentiation and inhibit Notch signalling of primary human GBM cells also in this in vivo set-up. In conclusion, these findings shed light on an unsuspected crosstalk between hypoxia, Wnt and Notch signalling in GBM, and suggest the potential to manipulate these microenvironmental signals to blunt GBM malignancy.
authors: Department of Woman and Child Health, University of Padova, Padova, Italy.
authors: E
authors: E
authors: Rampazzo
authors: L
authors: L
authors: Persano
authors: F
authors: F
authors: Pistollato
authors: E
authors: E
authors: Moro
authors: C
authors: C
authors: Frasson
authors: P
authors: P
authors: Porazzi
authors: A
authors: A
authors: Della Puppa
authors: S
authors: S
authors: Bresolin
authors: G
authors: G
authors: Battilana
authors: S
authors: S
authors: Indraccolo
authors: G
authors: G
authors: Te Kronnie
authors: F
authors: F
authors: Argenton
authors: N
authors: N
authors: Tiso
authors: G
authors: G
authors: Basso
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000378:metabolism; D015687:Cell Hypoxia; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007814:Larva / Q000235:genetics / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis; D051880:Receptors, Notch / Q000378:metabolism; D015996:Survival Rate; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D015027:Zebrafish / Q000254:growth & development; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051880:Receptors, Notch; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D051153:Wnt Proteins; D051176:beta Catenin