Deciphering the molecular mechanism of Wnt trafficking in gastric cancer

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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.