Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma

Jing Hao, Xiangzi Han, Haidong Huang, Xingjiang Yu, Jiankang Fang, Jianjun Zhao, Richard A. Prayson, Shideng Bao and Jennifer S. Yu ()
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Jing Hao: Lerner Research Institute, Cleveland Clinic
Xiangzi Han: Lerner Research Institute, Cleveland Clinic
Haidong Huang: Lerner Research Institute, Cleveland Clinic
Xingjiang Yu: Lerner Research Institute, Cleveland Clinic
Jiankang Fang: Lerner Research Institute, Cleveland Clinic
Jianjun Zhao: Lerner Research Institute, Cleveland Clinic
Richard A. Prayson: Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic
Shideng Bao: Lerner Research Institute, Cleveland Clinic
Jennifer S. Yu: Lerner Research Institute, Cleveland Clinic

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-37397-w

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