A complex of Wnt/planar cell polarity signaling components Vangl1 and Fzd7 drives glioblastoma multiforme malignant properties.
A complex of Wnt/planar cell polarity signaling components Vangl1 and Fzd7 drives glioblastoma multiforme malignant properties.
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DOI：
10.1016/j.canlet.2023.216280
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发表时间：
2023-06
期刊：
影响因子：
9.7
通讯作者：
Courtney A. Dreyer;K. Vandervorst;Dean E. Natwick;George R. R. Bell-George-R.-R.-Bell-2067439090;Prachi Sood;M. Hernandez;J. Angelastro;Sean R. Collins;K. Carraway
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文献类型：
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作者：
Courtney A. Dreyer;K. Vandervorst;Dean E. Natwick;George R. R. Bell-George-R.-R.-Bell-2067439090;Prachi Sood;M. Hernandez;J. Angelastro;Sean R. Collins;K. Carraway
靶向患者多形性胶质母细胞瘤(GBM)的常见致癌驱动因素在很大程度上仍然无效，增加了替代途径可能有助于肿瘤侵袭性的可能性。在这里，我们证明了非规范WNT平面细胞极性(WNT/PCP)信号通路的组成部分Vangl1和FZD7通过驱动细胞的增殖、迁移和侵袭来促进GBM的恶性，并参与Rho GTP酶促进迁移的GBM细胞的细胞骨架重排和肌动蛋白动力学。从机制上讲，我们发现在迁移的GBM细胞的前沿存在一个新的Vangl1/FZD7复合体，并提出这个复合体对于招募下游效应分子促进肿瘤进展至关重要。此外，我们观察到，在小鼠颅内移植模型中，FZD7的缺失导致了显著的肿瘤生长和潜伏期的抑制，并延长了总体存活时间。我们的观察支持一种新的机制，即Wnt/PCP组件Vangl1和FZD7在迁移的GBM细胞的前沿形成复合体，参与促进肌动蛋白细胞骨架重排动力学的下游效应器。我们的研究结果表明，干扰Wnt/PCP通路的功能可能为诊断为GBM的患者提供一种新的治疗策略。
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 ofFZD7results 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.