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Recent evidence from the Scholpp lab suggested that Wnt/beta-catenin ligands are loaded on and distributed by signalling filopodia in vertebrate tissue (Stanganello et al., 2015). The generation and dynamic of this transport mechanism is regulated by components of the Wnt/PCP signalling pathway. Controlling Wnt trafficking will allow us to regulate Wnt signalling dependent cancers such as gastrointestinal cancers.
About
What is the therapeutic hypothesis? Gastrointestinal (GI) cancer refers to malignant conditions of the GI tract and accessory organs of digestion. Worldwide GI cancer is one of the most common cancers in terms of new cases including colorectal (945 000), stomach (876 000), and liver (564 000) in 2000. The GI epithelium is strongly dependent on the balance between cell proliferation, cell cycle arrest, and cell migration and this appears reflected in a high susceptibility to malignant transformation. What is the specific target or pathway? The Wnt signalling network plays a crucial role in regulating these processes in several organs, but it’s role in the gastric mucosa is poorly understood. The canonical Wnt/β-catenin branch is activated in more than 30% of gastric cancer tissues leading to the upregulation of several components of the Wnt pathways such as effectors of the actin cytoskeleton in gastric cancer. Furthermore, Wnt/β-catenin signalling is essential for the self-renewal of gastric cancer stem cells leading to Wnt-mediated resistance to apoptosis, which may explain the increasing number of recurrence of these primary tumours. Complementary, the non-canonical, β-catenin independent branch plays a similar important role. The non-canonical key ligands, such as Wnt5a, are upregulated in gastric cancer regardless of the histological phenotype and it is correlated with poor prognosis. It is unknown how these signalling branches cooperate during gastric carcinogenesis. What is the current project status and enabling expertise to support the project? Recent evidence from the Scholpp lab suggested that canonical Wnt ligands are loaded on and distributed by signalling filopodia in vertebrate tissue (Stanganello et al., 2015). The generation and dynamic of this transport mechanism is regulated by components of the non-canonical Wnt signalling pathway. In a kinome-wide screen the Scholpp lab has identified several kinases which regulates the emergence of signalling filopodia. Preliminary data suggest that one of these kinases - a receptor tyrosine kinase (RTK) - regulates the number and length of Wnt signalling filopodia in cell culture and in the vertebrate model organism zebrafish. Furthermore, this RTK regulates non-canonical Wnt signalling. Preliminary data indicate that this RTK regulates Wnt transport in various cancer cell lines. Genetic blockage of this RTK reduces significantly proliferation of e.g. human gastric cancer cells and the survival of murine intestinal crypt organoids. What is the tractability of the proposition? We are interested in the molecular mechanism regulating cytoneme based trafficking of Wnt proteins in vertebrate tissue. We have identified a RTK in the plasma membrane of Wnt producing cells. Activation of this RTK leads to an increase in signalling filopodia. Our aim is twofold: First, we will investigate the molecular mechanism, the downstream signalling cascade as well as cytoskeletal machinery involved in this process. Second, we will undertake a compound screen of a chemical library for regulators of the identified kinases in gastric cancer organoids and the zebrafish in vivo system. What is the requirement for the industrial contribution? We would need access to a chemical library to perform the aforementioned screen, support of personnel and consumable costs. We could envisage to apply for external funding together with the industrial partner e.g. RCUK CASE studies.
Key Benefits
The genetics of multistep gastrointestinal (GI) carcinogenesis has been extensively studied over the last few decades, and frequent alterations of Wnt signaling genes in GI cancer were already recognized as early as the 1990s. Canonical Wnt/β-catenin signaling regulates cell fate determination, cell polarity, differentiation, and apoptosis, and it is now evident that active Wnt signaling is a major force driving GI carcinogenesis. In this project we envisage to pharmacologically block the pathway, by regulating the extracellular transport. Indeed, we have identified several kinases regulating Wnt transport. Targeting this kinase protein by the discovery of small-molecule inhibitors will have a strong benefit in anti-tumor therapy.
Applications
Treatment of Wnt/beta-catenin signalling dependent cancers by regulating extracellular Wnt trafficking.