Network and topological modelling of transition states in the Wnt signalling pathway.

Understanding how biological signals are communicated within cells and the complex decision making they support, requires a very precise knowledge of individual pathways and of their role in the wider signalling network. This project will develop and adapt recently developed graph theoretic and topological tools to unravel the complex relationships between different types of Wnt signalling. Wnt signalling is a key pathway that regulates many of the most fundamental cellular processes such as cell expansion and proliferation, cell fate decisions and cell migration. Wnt signalling is dysregulated in many diseases and is often a driver of tumour development. Two related types of Wnt signalling are known, canonical and non-canonical, and whilst both types use many of the same protein components, their functions and activity can be quitedistinct. Several studies have shown that there are complex interrelationships between canonical and noncanonical Wnt signalling , with cells and tissues switching between these modes (Florian et al, Nature, 2013; Upadhyay et al, PLoS Genetics, 2018; Ewing et al, J. Proteome Research, 2018). In this project, we will identify the underlying mechanisms controlling the transitions between these two modes of Wnt signalling by reconstructing the underlying dynamics from experimental observations (single-cell RNA-Seq and bulk gene-expression data). Namely, our project combines network modelling and topology: we superimpose experimental single-cell gene expression data on known regulatory interaction networks to obtain a distance measure that takes into account the directed network structure, and then reconstruct the topology of the underlying dynamical system from these distances. This will allow the identification of transition states between the different signalling modes and to prioritise them for experimental/laboratory study. We will then use wellcharacterized cell-based models of Wnt signalling activity in colorectal cancer (Ewing lab) or in haemopoietic stemcells (Morgan lab) to test and validate the predicted underlying biological mechanisms.
The ultimate goal is to develop a fundamental understanding of Wnt signalling and of different modes of Wnt signalling in cancer. Although focused on Wnt signalling, we expect the results of this PhD project to be widely applicable to other biological signalling networks.