Deciphering the molecular mechanism of Wnt trafficking in gastric cancer

因为放松管制会导致胃癌（GC）等毁灭性疾病，因此保持胃肠粘膜的稳定是至关重要的。事实上，全球每年确诊70万例胃癌是第三大癌症。然而，我们对健康和患病状态下胃肠道的生物学知识存在根本性的差距。这反映在用于治疗胃癌的靶向治疗相对较少的数量上。迫切需要了解调节胃内稳态的分子和细胞事件，以及这些事件在胃癌发生过程中是如何改变的。在胃肠道中保持平衡的一个重要的信号蛋白家族是Wnt信号家族。wnt调节许多重要的细胞过程：例如，wnt可以决定细胞分裂（细胞增殖）的速度；wnt可以决定细胞的命运（细胞分化）；wnt可以控制细胞的运动（细胞迁移）。因此，Wnt信号是组织生长、伤口愈合和消化道再生的基础。异常的Wnt信号传导与许多癌症有关。最近的癌症图谱将Wnt信号网络置于胃癌发生和发展的中心阶段。因此，了解Wnt信号通路对于开发对抗GC的新策略非常重要。Wnt信号级联的激活取决于细胞外Wnt信号蛋白的可用性。Wnt蛋白是由小的、明确的细胞群产生和分布的。相邻的更大的细胞群对信号做出反应，例如增加增殖。因此，网络的正确激活在很大程度上取决于Wnt蛋白从产生细胞到应答细胞群的精确传递。目前，我们还不清楚Wnt蛋白是如何在细胞间运输的，本研究旨在解决这一重大的理解空白。首席研究员最近的工作揭示了Wnt蛋白存在一种意想不到的转运机制。特异的指状细胞膜突起将Wnt蛋白转运到邻近细胞，并控制其中的Wnt信号激活。这些信号突起形成的障碍在组织发育过程中具有严重的后果——靶细胞不能按照其在组织中的位置遵循正确的细胞命运，导致组织畸形和不受控制的生长。本项目的中心假设是解除Wnt贩运的管制促进胃癌肿瘤的发生和生长。我们假设这些“信号细胞指”的数量对Wnt信号激活的幅度至关重要。细胞突起数量越多，说明特定组织中Wnt蛋白的数量越多，组织生长速度越快。阻断信号突出导致Wnt运输减少，从而降低组织生长。为了解决这些假设，我们将使用最先进的遗传策略结合先进的二维和三维组织培养方法中的癌细胞成像技术。我们在这个领域处于国际领先地位，因为我们已经开发出必要的技术来测试这个新假设。我们将(1)研究细胞外Wnt运输，(2)分析调节Wnt运输的分子机制，(3)筛选操纵GC中Wnt运输的化学物质。这一基本的新知识将为通过操纵Wnt蛋白转运，以一种完全不同的方式控制GC肿瘤生物学中Wnt信号级联的活性提供基础。

Keeping the gastrointestinal lining in a stable state is fundamental because deregulation can lead to devastating diseases such as gastric cancer (GC). Indeed, world-wide 700,000 cases are diagnosed per year and GC is the third most cancer. However, there is a fundamental gap in our knowledge about the biology of the gastrointestinal tract in its healthy and diseased states. This is reflected by the relatively low number of targeted therapies available to treat GC. There is an urgent need to understand the molecular and cellular events regulating gastric homeostasis, and how these are altered during gastric carcinogenesis. An important family of signalling proteins keeping balance in the gastrointestinal tract is the Wnt signalling family. Wnts regulate many vital cellular processes: Wnts can, for instance, determine how fast cells divide (cellular proliferation); Wnts can dictate the fate of cells (cellular differentiation); and Wnts can control movement of cells (cellular migration). Wnt signalling is therefore fundamental to tissue growth, wound healing, and regeneration in the digestive tract. Aberrant Wnt signalling has been linked to many cancers. The recent cancer atlas has placed the Wnt signalling network at centre stage in GC initiation and progression. Therefore, it is important to understand the Wnt signalling pathway to develop novel strategies to fight GC. The activation of the Wnt signalling cascade depends on the availability of extracellular Wnt signalling proteins. Wnt proteins are produced and distributed from small, defined cell groups. Adjacent, larger groups of cells then respond to the signal by, for example, increased proliferation. Proper activation of the network is therefore largely dependent on the precise delivery of Wnt proteins from producing cells to a population of responding cells. Currently, we do not understand how Wnt proteins are transported between cells and this proposal aims to address this significant gap in understanding. Recent work by the Principal Investigator has revealed the existence of an unexpected transport mechanism for Wnt proteins. Specific finger-like cell membrane protrusions transport Wnt proteins to neighbouring cells and control Wnt signal activation therein. Impairments in the formation of these signalling protrusions has severe consequences during tissue development - target cells do not follow their correct cellular fate according to their position in a tissue, leading to malformation and uncontrolled growth of tissues. The central hypothesis of this project is that deregulation of Wnt trafficking promotes initiation and growth of GC tumours. We hypothesize that the number of these "signalling cell fingers" is crucial for the amplitude of Wnt signal activation. The greater the number of cellular protrusions, the greater is the number of Wnt proteins in a particular tissue, and the faster is tissue growth. Decrease of Wnt transport by blockage of signalling protrusion would reduce tissue growth. To address these hypotheses, we will use state-of-the-art genetic strategies combined with advanced imaging techniques of cancer cells in 2D and in 3D tissue culture approaches.We have an international lead in this area because we have developed the required techniques to test this new hypothesis. We will (1) study extracellular Wnt trafficking, (2) analyse the molecular mechanisms regulating Wnt transport, and (3) screen for chemicals to manipulate Wnt trafficking in GC. This fundamental new knowledge will provide the basis to control the activity of Wnt signalling cascades in GC tumour biology in a radically different way, by manipulating Wnt protein transport.