IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37397-w.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37397-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-37397-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ravinder K. Bahia & Xiaoguang Hao & Rozina Hassam & Orsolya Cseh & Danielle A. Bozek & H. Artee Luchman & Samuel Weiss, 2023. "Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Lihui Liu & Ziyang Liu & Qinghua Liu & Wei Wu & Peng Lin & Xing Liu & Yuechuan Zhang & Dongpeng Wang & Briana C. Prager & Ryan C. Gimple & Jichuan Yu & Weixi Zhao & Qiulian Wu & Wei Zhang & Erzhong Wu, 2023. "LncRNA INHEG promotes glioma stem cell maintenance and tumorigenicity through regulating rRNA 2’-O-methylation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Francesco Antonica & Lucia Santomaso & Davide Pernici & Linda Petrucci & Giuseppe Aiello & Alessandro Cutarelli & Luciano Conti & Alessandro Romanel & Evelina Miele & Toma Tebaldi & Luca Tiberi, 2022. "A slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Ana Nikolic & Francesca Maule & Anna Bobyn & Katrina Ellestad & Seungil Paik & Sajid A. Marhon & Parinaz Mehdipour & Xueqing Lun & Huey-Miin Chen & Claire Mallard & Alexander J. Hay & Michael J. Johns, 2023. "macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    5. Jun Liu & Xiaoying Wang & Ann T. Chen & Xingchun Gao & Benjamin T. Himes & Hongyi Zhang & Zeming Chen & Jianhui Wang & Wendy C. Sheu & Gang Deng & Yang Xiao & Pan Zou & Shenqi Zhang & Fuyao Liu & Yong, 2022. "ZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    6. Cathy Pichol-Thievend & Oceane Anezo & Aafrin M. Pettiwala & Guillaume Bourmeau & Remi Montagne & Anne-Marie Lyne & Pierre-Olivier Guichet & Pauline Deshors & Alberto Ballestín & Benjamin Blanchard & , 2024. "VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    7. Michelle M. Kameda-Smith & Helen Zhu & En-Ching Luo & Yujin Suk & Agata Xella & Brian Yee & Chirayu Chokshi & Sansi Xing & Frederick Tan & Raymond G. Fox & Ashley A. Adile & David Bakhshinyan & Kevin , 2022. "Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    8. Tatenda Mahlokozera & Bhuvic Patel & Hao Chen & Patrick Desouza & Xuan Qu & Diane D. Mao & Daniel Hafez & Wei Yang & Rukayat Taiwo & Mounica Paturu & Afshin Salehi & Amit D. Gujar & Gavin P. Dunn & Ni, 2021. "Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37397-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.