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Published on: October 27, 2014
A complex of Wnt/planar cell polarity signaling components Vangl1 and Fzd7 drives glioblastoma multiforme malignant
Courtney A Dreyer1, Kacey VanderVorst1, Dean Natwick2
1Department of Biochemistry and Molecular Medicine and University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, USA.
Abstract:
Targeting common oncogenic drivers of glioblastoma multiforme (GBM) in patients has remained largely ineffective, raising the possibility that alternative pathways may contribute to tumor aggressiveness. Here we demonstrate that Vangl1 and Fzd7, components of the non-canonical Wnt planar cell polarity (Wnt/PCP) signaling pathway, promote GBM malignancy by driving cellular proliferation, migration, and invasiveness, and engage Rho GTPases to promote cytoskeletal rearrangements and actin dynamics in migrating GBM cells. Mechanistically, we uncover the existence of a novel Vangl1/Fzd7 complex at the leading edge of migrating GBM cells and propose that this complex is critical for the recruitment of downstream effectors to promote tumor progression. Moreover, we observe that depletion of FZD7 results in a striking suppression of tumor growth and latency and extends overall survival in an intracranial mouse xenograft model. Our observations support a novel mechanism by which Wnt/PCP components Vangl1 and Fzd7 form a complex at the leading edge of migratory GBM cells to engage downstream effectors that promote actin cytoskeletal rearrangements dynamics. Our findings suggest that interference with Wnt/PCP pathway function may offer a novel therapeutic strategy for patients diagnosed with GBM.
Insights
The Wnt/planar cell polarity pathway, involving Vangl1 and Fzd7, drives glioblastoma multiforme (GBM) aggressiveness. Targeting this pathway may offer new therapeutic strategies for GBM cancer.
Area of Science:
- Neuro-oncology
- Molecular signaling pathways
- Cell biology
Background:
- Targeting common oncogenic drivers in glioblastoma multiforme (GBM) has shown limited success.
- Alternative pathways contributing to GBM aggressiveness are being investigated.
- The non-canonical Wnt planar cell polarity (Wnt/PCP) pathway is a potential area of interest.
Purpose of the Study:
- To investigate the role of Vangl1 and Fzd7, components of the Wnt/PCP pathway, in GBM malignancy.
- To elucidate the molecular mechanisms by which Wnt/PCP signaling promotes GBM progression.
- To evaluate the therapeutic potential of targeting the Wnt/PCP pathway in GBM.
Main Methods:
- Analysis of Vangl1 and Fzd7 expression and function in GBM cells.
- Investigation of the interaction between Vangl1, Fzd7, and Rho GTPases.
- Assessment of cytoskeletal rearrangements and actin dynamics in migrating GBM cells.
- Evaluation of tumor growth, latency, and survival in an intracranial mouse xenograft model following FZD7 depletion.
Main Results:
- Vangl1 and Fzd7 promote GBM proliferation, migration, and invasiveness.
- The Wnt/PCP pathway engages Rho GTPases for cytoskeletal rearrangements in migrating GBM cells.
- A novel Vangl1/Fzd7 complex forms at the leading edge of migrating GBM cells.
- Depletion of FZD7 significantly suppresses tumor growth, reduces latency, and extends survival in a mouse model.
Conclusions:
- Vangl1 and Fzd7 are key mediators of GBM malignancy through the Wnt/PCP pathway.
- A Vangl1/Fzd7 complex at the leading edge is critical for recruiting downstream effectors and promoting tumor progression.
- Targeting the Wnt/PCP pathway represents a promising novel therapeutic strategy for glioblastoma multiforme.
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