Wnt pathway intracellular effectors are key deciders of GBM cell phenotype and behaviour.
Elena Rampazzo, University of Padova, Institute of Pediatric Research – IRP corso Stati Uniti 4, 35127, Padova, Italy; Daniele Boso, University of Padova, corso Stati Uniti 4, 35127, Padova, Italy; Francesca Maule, University of Padova, corso Stati Uniti 4, 35127, Padova, Italy; Alessandro Della Puppa, University Hospital of Padova, Padova, Italy; Giuseppe Basso, University of Padova, corso Stati Uniti 4, 35127, Padova, Italy; Luca Persano, University of Padova, Institute of Pediatric Research – IRP corso Stati Uniti 4, 35127, Padova, Italy
Recent researches have contributed to the notion that brain tumors, including Glioblastoma (GBM) arise from a specific subset of cells defined as neural cancer stem cells (CSCs) that are also responsible for tumor progression and relapse. These cells have been reported to reside in peculiar microenvironments such as hypoxic niches able to sustain their aggressive phenotype. Indeed, also adult neural stem cells reside in specific brain niches characterized by low oxygen tensions in which Wnt activation drives their neuronal differentiation.
In this study, we questioned if Wnt activation could drive neuronal differentiation also in GBM stem cells and, in particular, we investigate the specific role that different intracellular Wnt effectors exert in modulating GBM derived cells phenotype.
We demonstrated that Wnt pathway activation under hypoxia was able to induce neuronal differentiation of GBM stem cells. Intriguingly, we found that, after Wnt3a treatment, β-catenin preferentially bound to the co-factor TCF-7 (also known as TCF-1) in hypoxia and to the cofactor TCF7L2 (also known as TCF-4) in normoxia. Moreover, β-catenin and TCF-7 were associated to HIF-1α, while TCF7L2 did not. All together these data give strength to our hypothesis indicating that intra-cellular effectors of Wnt signalling, such as β-catenin, bind to different co-factors in response to the cellular microenvironment. In particular, we demonstrated that oxygen tension determines the choice between TCF-7 and TCF7L2 recruitment. Indeed, at low O2, we found β-catenin- and TCF1-mediated transcription as strongly regulated by HIF-1α and able to activate the pro-neuronal genes NEUROD1 and NEUROG1. Conversely, the binding and activation of β-catenin- and TCF4-mediated transcription increase GBM cell proliferation.
These data increase the knowledge about the epistatic relationship occurring among hypoxia and Wnt signalling in GBM stem cells. Moreover, we demonstrate as a different combination of the same transcription factors could control multiple, even also conflicting, intracellular functions.