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Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119166/ https://www.ncbi.nlm.nih.gov/pubmed/37080989 http://dx.doi.org/10.1038/s41467-023-37397-w |
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author | Hao, Jing Han, Xiangzi Huang, Haidong Yu, Xingjiang Fang, Jiankang Zhao, Jianjun Prayson, Richard A. Bao, Shideng Yu, Jennifer S. |
author_facet | Hao, Jing Han, Xiangzi Huang, Haidong Yu, Xingjiang Fang, Jiankang Zhao, Jianjun Prayson, Richard A. Bao, Shideng Yu, Jennifer S. |
author_sort | Hao, Jing |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10119166 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-101191662023-04-22 Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma Hao, Jing Han, Xiangzi Huang, Haidong Yu, Xingjiang Fang, Jiankang Zhao, Jianjun Prayson, Richard A. Bao, Shideng Yu, Jennifer S. Nat Commun Article 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. Nature Publishing Group UK 2023-04-20 /pmc/articles/PMC10119166/ /pubmed/37080989 http://dx.doi.org/10.1038/s41467-023-37397-w Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Hao, Jing Han, Xiangzi Huang, Haidong Yu, Xingjiang Fang, Jiankang Zhao, Jianjun Prayson, Richard A. Bao, Shideng Yu, Jennifer S. Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma |
title | Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma |
title_full | Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma |
title_fullStr | Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma |
title_full_unstemmed | Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma |
title_short | Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma |
title_sort | sema3c signaling is an alternative activator of the canonical wnt pathway in glioblastoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119166/ https://www.ncbi.nlm.nih.gov/pubmed/37080989 http://dx.doi.org/10.1038/s41467-023-37397-w |
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