Living Systems Institute, School of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom.
The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom.
Elife. 2022 Aug 30;11:e77376. doi: 10.7554/eLife.77376.
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.
Wnt/β-catenin 信号通路在发育和许多疾病（包括细胞增殖、迁移和分化）中调节多种细胞过程。尽管 Wnt 蛋白具有疏水性，但它们可以远距离发挥作用，诱导旁分泌信号。最近的研究已经确定了几个参与 Wnt 分泌的因素；然而，我们对 Wnt 配体如何在细胞间运输以与其同源受体相互作用的理解仍存在争议。在这里，我们证明胃癌细胞利用纤毛将 Wnt3 细胞间运输以促进增殖和细胞存活。此外，我们确定了膜结合支架蛋白 Flotillin-2（Flot2），它在胃癌中经常过表达，是这些纤毛的调节剂。与 Wnt 共受体和纤毛起始因子 Ror2 一起，Flot2 决定了胃癌中 Wnt3 纤毛的数量和长度。最后，我们表明 Flotillins 对于斑马鱼胚胎发生过程中的 Wnt8a 纤毛也是必需的，这表明在发育和疾病中，Flotillin 介导的 Wnt 运输在纤毛上具有保守的机制。
