The scaffolding protein flot2 promotes cytoneme-based transport of wnt3 in gastric cancer

Author:

Routledge Daniel1ORCID,Rogers Sally1,Ono Yosuke1,Brunt Lucy1,Meniel Valerie2,Tornillo Giusy2,Ashktorab Hassan3,Phesse Toby J24ORCID,Scholpp Steffen1ORCID

Affiliation:

1. Living Systems Institute, School of Biosciences, College of Life and Environmental Sciences, University of Exeter

2. The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University

3. Department of Medicine, Howard University

4. The Peter Doherty Institute for Infection and Immunity, The University of Melbourne

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.

Funder

Medical Research Council

Biotechnology and Biological Sciences Research Council

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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