Canonical and non-canonical Wnt signaling pathways control the stem-like behavior of human gliomas


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Teodoro Pulvirenti1, Maartje Van Der Heijden2, Viviane Tabar2, Alan Hall1
1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, United States,2Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, United States

Background

Glioblastoma multiforme, the most common glioma variant in adults, is currently considered the most malignant and lethal brain tumor. The available evidence in the literature suggest that these tumors are initiated and maintained by a small fraction of cancer stem cells. In neural stem cells, the decision to divide or differentiate is strongly influenced by Wnt signaling. Interestingly, mutations in Wnt signaling pathways have been found in a subgroup of medulloblastomas, although their role in gliomas still remains unclear.

Method

To explore the role of Wnt signaling in human gliomas, we used lentiviral shRNA vectors targeting Disheveled (Dvl). We examined the ability of Dvl depleted cells to form non-adherent neurospheres in serum-free media supplemented with EGF and FGF. Dvl depleted cells were also stereotactically injected in the straitum of NOD/SCID mice to investigate their tumorigenicity. Tumor analysis was performed using Magnetic Resonance Imaging and subsequent immunostaining of brain cryo-sections.

Results

In this study we show a role for Wnt signaling in influencing the decision of stem-like glioma cells to proliferate or differentiate. Depletion of Dvl, a key mediator of Wnt signaling, inhibits cell proliferation and induces differentiation of stem-like glioma cells.  Dvl depleted cells lose their ability to form neurospheres in neural stem cell medium, show a decrease in the neural stem cell marker Nestin and their implantation in mice brain revealed a loss of tumorigenic ability. Furthermore, here we show that blocking the canonical Wnt/b-catenin pathway affects proliferation but is not sufficient to induce differentiation. More interestingly, we have identified an additional, non-canoncial Wnt pathway required for glioma proliferation, involving Wnt5a, the tyrosine kinase receptor Ror2 and the downstream signaling mediator Daam1.

Conclusion

Together these results suggest that both canonical and non-canonical signaling pathways cooperate to maintain the proliferative capacity of human glioblastomas, and inhibition of both is required to promote differentiation.