There is an urgent need to understand the cellular signalling network because it is fundamental to the maintenance of a stable state of mature tissue. Deregulation of this network leads to devastating diseases such as the initiation and growth of tumours. The Wnt signalling pathway contributes to this important signalling network and aberrant activation of Wnt signalling is a major driver of gastric cancer growth and metastasis.
Despite three decades of Wnt research, we are still not able to explain how Wnt ligands are disseminated in a tissue, which is a prerequisite to control the Wnt network effectively during disease. Recently, our work has revealed the existence of an unexpected transport mechanism for Wnt proteins, which changes the way we understand how ligands spread in tissues: Wnt is rapidly loaded on thin cellular extensions to be transferred to target cells for signal activation. However, the mechanism controlling Wnt signalling protrusions is currently unknown. By closing this gap in our understanding of Wnt transport, we will enable the development of novel approaches to control Wnt signalling in malignancies like gastric cancer.
This project will provide new understandings of extracellular Wnt protein trafficking at the molecular, cellular and tissue level. Our hypothesis, supported by preliminary data, is that activating the Wnt pathway in the Wnt-producing cells reinforces formation of signal protrusions and thus Wnt signal activation in the neighbouring tissue. This will enable us to understand how Wnt signalling spreads through the tissue to induce proliferation in GC. To test our hypothesis, we will analyse the mechanism of Wnt trafficking and analyse the effect of drugs that limit Wnt signalling protrusions to control tumour growth.
The results of this multiscale, multidisciplinary project will provide a step change in understanding how the Wnt signalling pathway operates in gastric cancer. We are grateful that the Medical Research Council (MRC) recognizes the importance of Wnt trafficking in cancer development and will fund this project in the next three years.
