Center for Cancer Stem Cell Biology, Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
Department of Anatomic Pathology, Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA.
Nat Commun. 2023 Apr 20;14(1):2262. doi: 10.1038/s41467-023-37397-w.
The Wnt pathway is frequently dysregulated in many cancers, underscoring it as a therapeutic target. Wnt inhibitors have uniformly failed in clinical trials. Here, we report a mechanism of WNT pathway activation through the Semaphorin 3 C neurodevelopmental program in glioma stem-like cells. Sema3C directs β-catenin nuclear accumulation in a Rac1-dependent process, leading to transactivation of Wnt target genes. Sema3C-driven Wnt signaling occurred despite suppression of Wnt ligand secretion, suggesting that Sema3C drives canonical Wnt signaling independent of Wnt ligand binding. In a mouse model of glioblastoma, combined depletion of Sema3C and β-catenin partner TCF1 extended animal survival more than single target inhibition alone. In human glioblastoma, Sema3C expression and Wnt pathway activation were highly concordant. Since Sema3C is frequently overexpressed in glioblastoma, Sema3C signaling may be a significant mechanism of resistance to upstream Wnt pathway inhibitors. Dual targeting of Sema3C and Wnt pathways may achieve clinically significant Wnt pathway inhibition.
Wnt 通路在许多癌症中经常失调，这突显了它作为治疗靶点的重要性。Wnt 抑制剂在临床试验中均告失败。在这里，我们报告了一种通过神经发育程序 Semaphorin 3C 在神经胶质瘤干细胞中激活 WNT 通路的机制。Sema3C 通过 Rac1 依赖性过程指导β-连环蛋白的核积累，导致 Wnt 靶基因的反式激活。尽管抑制了 Wnt 配体的分泌，但 Sema3C 驱动的 Wnt 信号仍然发生，这表明 Sema3C 驱动经典的 Wnt 信号不依赖于 Wnt 配体结合。在胶质母细胞瘤的小鼠模型中，Sema3C 和β-连环蛋白伙伴 TCF1 的联合耗竭比单独抑制单一靶标延长动物存活时间更长。在人类胶质母细胞瘤中，Sema3C 的表达和 Wnt 通路的激活高度一致。由于 Sema3C 在胶质母细胞瘤中经常过表达，因此 Sema3C 信号可能是对上游 Wnt 通路抑制剂产生耐药性的重要机制。Sema3C 和 Wnt 通路的双重靶向可能实现临床上显著的 Wnt 通路抑制。
