The scaffolding protein Flot2 promotes cytoneme-based transport of Wnt3 in gastric cancer
- University of Exeter, United Kingdom
- Cardiff University, United Kingdom
- Howard University, United States
Abstract
The Wnt/β-catenin signalling pathway regulates multiple cellular processes during development and many diseases, including cell proliferation, migration, and differentiation. Despite their hydrophobic nature, Wnt proteins exert their function over long distances to induce paracrine signalling. Recent studies have identified several factors involved in Wnt secretion, however, our understanding of how Wnt ligands are transported between cells to interact with their cognate receptors is still debated. Here, we demonstrate that gastric cancer cells utilise cytonemes to transport Wnt3 intercellularly to promote proliferation and cell survival. Furthermore, we identify the membrane-bound scaffolding protein Flotillin-2 (Flot2), frequently overexpressed in gastric cancer, as a modulator of these cytonemes. Together with the Wnt co-receptor and cytoneme initiator Ror2, Flot2 determines the number and length of Wnt3 cytonemes in gastric cancer. Finally, we show that Flotillins are also necessary for Wnt8a cytonemes during zebrafish embryogenesis, suggesting a conserved mechanism for Flotillin-mediated Wnt transport on cytonemes in development and disease.
Data availability
All data generated or analysed during this study are included in the manuscript, supporting files and source files; Supporting Data files and Source Data have been provided to all figures.
Article and author information
Author details
Funding
Medical Research Council (MR/N0137941/1)
- Daniel Routledge
Medical Research Council (MR/S007970/1)
- Sally Rogers
- Steffen Scholpp
Biotechnology and Biological Sciences Research Council (BB/S016295/1)
- Yosuke Ono
- Lucy Brunt
- Steffen Scholpp
Medical Research Council (MR/R026424/1)
- Valerie Meniel
- Giusy Tornillo
- Toby Phesse
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Julia Christina Gross, Health and Medical University
Ethics
Animal experimentation: Zebrafish care and all experimental procedures were carried out in accordance with the European Communities Council Directive (2010/63/EU) and Animals Scientific Procedures Act (ASPA) 1986. Zebrafish experimental procedures were carried out under personal and project licenses granted by the UK Home Office under ASPA, and ethically approved by the Animal Welfare and Ethical Review Body at the University of Exeter.
Version history
- Preprint posted: January 8, 2022 (view preprint)
- Received: January 26, 2022
- Accepted: August 27, 2022
- Accepted Manuscript published: August 30, 2022 (version 1)
- Version of Record published: September 8, 2022 (version 2)
Copyright
© 2022, Routledge et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The scaffolding protein Flot2 promotes cytoneme-based transport of Wnt3 in gastric cancer
eLife 11:e77376.
https://doi.org/10.7554/eLife.77376
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