Sema3C Signaling as an Alternative Activator of Canonical Wnt Signaling in Glioblastoma

项目总结 Wnt通路在许多癌症中经常被失调，强调它是一种治疗方法 目标。尽管Wnt抑制剂在许多临床前研究中看起来很有希望，但它们已经失败了 在临床试验中统一使用。耐药的分子机制还不清楚。进一步 对特定肿瘤类型中WNT途径激活的确切机制进行了剖析 需要开发毒性较小的新的WNT途径抑制剂。轴突引导程序 Sema3C/PlxnD1促进胶质瘤干细胞的自我更新和致瘤性 但潜在的机制尚不清楚。我们的数据现在表明Sema3C/PlxnD1信号 作为规范WNT信号的替代激活剂。重要的是，Sema3C驱动的WNT 尽管Wnt配体的分泌受到抑制，信号还是发生了，这表明Sema3C可能 驱动规范的Wnt信号，不依赖于Wnt与其受体的结合。作为Sema3C/PlxnD1 超过85%的GBM使用信号转导，这可能是抗病的一个重要机制 上游Wnt途径抑制物。我们的数据支持Sema3C/PlxnD1信号调节两个 Wnt信号的关键方面：β-连环蛋白的稳定性和核转位。在这份提案中， 我们的目标是确定Sema3C/PlxnD1调控规范Wnt的分子机制 发信号。此外，我们的目标是评估靶向Sema3C信号转导的治疗效果。 提高小鼠肾小球基底膜模型对上游Wnt抑制剂的敏感性。这些研究将 提供了一种新的治疗策略，以实现临床上显著的Wnt通路抑制 GSCs可能没有目前可用的WNT抑制剂的毒性。这些研究可能是 适用于同时利用Sema3C和Wnt的其他癌症，包括乳腺癌和前列腺癌 发信号。

PROJECT SUMMARY The Wnt pathway is frequently dysregulated in many cancers, underscoring it as a therapeutic target. Although Wnt inhibitors appear promising in many preclinical studies, they have failed uniformly in clinical trials. Molecular mechanisms of resistance are poorly defined. Further dissection of the precise mechanisms of WNT pathway activation in specific tumor types is needed to develop new WNT pathway inhibitors with less toxicity. The axonal guidance program Sema3C/PlxnD1 promotes the self-renewal and tumorigenicity of glioma stem-like cells (GSCs), but the underlying mechanisms are unclear. Our data now suggest that Sema3C/PlxnD1 signaling functions as an alternative activator of canonical Wnt signaling. Importantly, Sema3C-driven Wnt signaling occurred despite suppression of Wnt ligand secretion, suggesting that Sema3C may drive canonical Wnt signaling independent of Wnt binding to its receptors. As Sema3C/PlxnD1 signaling is used in over 85% of GBM, it may represent an important mechanism of resistance to upstream Wnt pathway inhibitors. Our data support that Sema3C/PlxnD1 signaling regulates two critical aspects Wnt signaling: beta-catenin stability and nuclear translocation. In this proposal, we aim to identify molecular mechanisms by which Sema3C/PlxnD1 regulate canonical Wnt signaling. Additionally, we aim to assess the therapeutic impact of targeting Sema3C signaling to improve sensitivity to upstream Wnt inhibitors in mouse models of GBM. These studies will provide a novel therapeutic strategy to achieve clinically significant Wnt pathway inhibition in GSCs potentially without the toxicity of currently available WNT inhibitors. These studies may be applied to other cancers including breast and prostate cancers that utilize both Sema3C and Wnt signaling.