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Deciphering the molecular mechanism of Wnt trafficking in gastric cancer

破译Wnt转运在胃癌中的分子机制

基本信息

批准号：
MR/S007970/1
负责人：
Steffen Scholpp
金额：
$ 69.66万
依托单位：
UNIVERSITY OF EXETER
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS007970%2F1
关键词：
Deciphering molecular mechanism Wnt trafficking

项目摘要

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.

保持胃肠道粘膜处于稳定状态是至关重要的，因为放松管制会导致胃癌（GC）等毁灭性疾病。事实上，全世界每年诊断出70万例病例，GC是第三大癌症。然而，我们对健康和疾病状态下胃肠道生物学的认识存在根本性的差距。可用于治疗GC的靶向疗法数量相对较少就反映了这一点。有一个迫切需要了解的分子和细胞的事件调节胃的稳态，以及如何改变这些在胃癌发生。在胃肠道中保持平衡的信号蛋白的一个重要家族是Wnt信号家族。Wnt调控许多重要的细胞过程：例如，Wnt可以决定细胞分裂的速度（细胞增殖）; 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信号传导是消化道中组织生长、伤口愈合和再生的基础。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GC起始和进展的中心阶段。因此，重要的是要了解Wnt信号通路，以开发新的策略来对抗GC。Wnt信号级联的激活取决于细胞外Wnt信号蛋白的可用性。Wnt蛋白由小的、确定的细胞群产生和分布。相邻的较大细胞群随后通过例如增加的增殖来响应信号。因此，网络的正确激活在很大程度上取决于Wnt蛋白从生产细胞到响应细胞群体的精确递送。目前，我们还不了解Wnt蛋白如何在细胞之间转运，这项提案旨在解决这一重大理解差距。首席研究员最近的工作揭示了Wnt蛋白质存在一种意想不到的转运机制。特异性指状细胞膜突起将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-靶细胞不能根据其在组织中的位置遵循其正确的细胞命运，导致组织的畸形和不受控制的生长。该项目的中心假设是Wnt运输的失调促进GC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。细胞突起的数量越多，特定组织中Wnt蛋白的数量越多，组织生长越快。通过阻断信号突起而减少Wnt转运将减少组织生长。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2D和3D组织培养方法中的癌细胞成像技术。我们在这一领域处于国际领先地位，因为我们已经开发出测试这一新假设所需的技术。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）筛选化学物质来操纵GC中的Wnt运输。这一基本的新知识将提供基础，以一种完全不同的方式，通过操纵Wnt蛋白转运，控制GC肿瘤生物学中Wnt信号级联的活性。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vangl2 regulates the dynamics of Wnt cytonemes in vertebrates

Vangl2 调节脊椎动物 Wnt 细胞因子的动态

DOI：
10.1101/2020.12.23.424142
发表时间：
2020
期刊：
影响因子：
0
作者：
Brunt L
通讯作者：
Brunt L

Development of the electric organ in embryos and larvae of the knifefish, Brachyhypopomus gauderio.

DOI：
10.1016/j.ydbio.2020.06.010
发表时间：
2020-10-01
期刊：
Developmental biology
影响因子：
2.7
作者：
Alshami IJJ;Ono Y;Correia A;Hacker C;Lange A;Scholpp S;Kawasaki M;Ingham PW;Kudoh T
通讯作者：
Kudoh T

Vertebrate Wnt5a - At the crossroads of cellular signalling.