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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...

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Autores principales: Hao, Jing, Han, Xiangzi, Huang, Haidong, Yu, Xingjiang, Fang, Jiankang, Zhao, Jianjun, Prayson, Richard A., Bao, Shideng, Yu, Jennifer S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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.
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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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