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

Author

Listed:
  • 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
    Neurological Institute, Cleveland Clinic)

  • Shideng Bao

    (Lerner Research Institute, Cleveland Clinic)

  • Jennifer S. Yu

    (Lerner Research Institute, Cleveland Clinic
    Neurological Institute, Cleveland Clinic
    Taussig Cancer Institute, Cleveland Clinic)

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.

Suggested Citation

  • Jing Hao & Xiangzi Han & Haidong Huang & Xingjiang Yu & Jiankang Fang & Jianjun Zhao & Richard A. Prayson & Shideng Bao & Jennifer S. Yu, 2023. "Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37397-w
    DOI: 10.1038/s41467-023-37397-w
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    1. Tracy S. Tran & Maria E. Rubio & Roger L. Clem & Dontais Johnson & Lauren Case & Marc Tessier-Lavigne & Richard L. Huganir & David D. Ginty & Alex L. Kolodkin, 2009. "Secreted semaphorins control spine distribution and morphogenesis in the postnatal CNS," Nature, Nature, vol. 462(7276), pages 1065-1069, December.
    2. Jian Chen & Yanjiao Li & Tzong-Shiue Yu & Renée M. McKay & Dennis K. Burns & Steven G. Kernie & Luis F. Parada, 2012. "A restricted cell population propagates glioblastoma growth after chemotherapy," Nature, Nature, vol. 488(7412), pages 522-526, August.
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