Scholpp Group


Contact-mediated signalling in development and disease

Group Members

Group LeaderPostdoctoral ResearchersPhD StudentsResearch Technicians
Steffen ScholppLucy Brunt
Yosuke Ono
Tom Piers
Sally Rogers
Emma Cooper
Michael Dawes
Kevin Fang
Gemma Sutton
Agnieszka Kaczmar

Cell-to-cell communication is essential for regulating the development of all multicellular organisms. Intercellular communication is based on chemical stimuli – including signalling proteins – which control the cellular behaviour in a tissue. An important family of signalling proteins that orchestrate development is the Wnt signalling family. Wnts regulate vital cellular processes, including how fast cells divide; the fate of cells or how to differentiate into different forms; and how cells move. Wnt signalling is therefore fundamental to the development of early life (e.g. embryogenesis), and organ development, but also during tissue homeostasis and thus crucial during wound healing and regeneration. Furthermore, we know that a relatively small and specific group of cells control and distribute Wnt proteins controlling development. Adjacent, larger groups of cells then respond to the signal. Wnt function is therefore dependent on the precise delivery of Wnt proteins from producing cells to responding cells.

Currently, how Wnt proteins are transported between cells to activate signalling is unknown. As such, we do not understand how the message is delivered from one cell to another. Our research aims to understand how the message is conveyed between cells.  Our research has revealed the existence of a completely unexpected cell-to-cell transport mechanism for Wnt proteins. Specific finger-like cell membrane protrusions – called cytonemes – carry Wnt proteins and transport them to neighbouring cells. After contact with the target cell, Wnt proteins are taken up by the responding cells. This process leads to signal activation in a target cell. Impairment of the number of Wnt protein transported on these signal protrusions leads to severe consequences during development, leading to malformation of tissues and severe developmental difficulties. Understanding the systems that govern this newly identified transport system is, therefore, fundamental for understanding how Wnt functions during embryogenesis and tissue homeostasis.

PhD Opportunities

LSI-funded PhD studentship

Title: Mechanistic analysis of direct cell-cell communication in organ development

Supervisors: Steffen Scholpp and Ge Guo

Wnt signalling is a major signalling network operating during development and tissue homeostasis. An array of ligands, receptors and co-receptors interact in the Wnt signalling network to orchestrate the precise downstream activation events cells. Importantly, biophysical parameters that control functional ligand-receptor interactions, and therefore affinities are central to achieving signalling specificity. So far, most studies aimed at quantification of Wnt ligand-Frizzled receptor binding affinities have relied on in vitro studies. However, these studies block out the influence of other Wnt ligands, receptors, co-receptors, structural proteins, and proteoglycans, which are present in the complex microenvironment in the living organism. 

The overall aim of this research project is to provide a quantitative analysis of ligand-receptor interactions of the Wnt signalling network under physiological conditions in vivo using standardised biophysical methods. To tackle this challenge, we will employ fluorescence correlation spectroscopy (FCS) as an advanced fluorescence technique in combination with the model organism zebrafish. 

FCS analyse involves the measurement of two-colour cross correlations from a very small detection volume. This method works in a very robust fashion in measurements of ligand-receptor interactions typically with an experimental time of a few hundred seconds. We have already developed an FCS protocol to measure the diffusion coefficient of signalling proteins (Yu et al., 2009, Nature) and binding affinities in zebrafish (Mattes et al., 2018 eLife, Brunt et al. 2021, Nat Comms). Recently, we have established a BBSRC funded, single-molecule detection platform, which allows FCS analysis.  

In this project, the student will measure the interactions between several Wnt signalling components with a prominent expression pattern in the zebrafish gastrula to establish a basis for a comparative analysis of binding affinities in the Wnt ligand-receptor network in vivo. First, we will analyse three Wnt ligands (Wnt5b, 8a, 11) and three Fzd receptors (Fzd7a, 7b, 8a). These proteins have been fluorescently tagged and their bioactivity has been confirmed. We will establish transgenic zebrafish lines with the aforementioned genes in their CRISPR/KO backgrounds. With our expertise, equipment, and tools, we are now in an excellent position to quantify ligand-receptor interactions of Wnt signalling components to allow a mechanistic insight into the process underlying Wnt receptor activation in the living zebrafish embryo 


MRC GW4 BioMed DTP PhD studentship

Title: Mechanistic analysis of direct cell-cell communication in organ development

Supervisors: Steffen Scholpp, Tobe Phesse, and Fabrice Gielen

Gastric cancer is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. There is an urgent need to develop novel therapeutic approaches to improve prognosis. A complex interplay in the tumour microenvironment promotes gastric cancer development. Deregulation of oncogenic cell signalling pathways such as the Wnt signalling pathway leads to the acquisition of malignant phenotypes, including tumour growth and metastasis. Mutations in Wnt- related tumour suppressor genes are closely associated with transforming normal gastric epithelium into adenomas. Concomitantly, elevated expression of Wnt ligands and receptors is essential for tumour progression. However, Wnt ligands and receptors are only expressed by a few cell types within the tumour tissue. Thus, there is a pressing need to improve our understanding of Wnt dissemination within a tumour.

Recently, we have broken new ground by showing that signalling filopodia, known as cytonemes, transport Wnt proteins in tissues (Stanganello et al., 2015, Nat Comms; Mattes et al., 2018, eLife; Brunt et al. 2021, Nat Comms). Our preliminary data suggest that cancer- associated fibroblasts and tumour cells produce different Wnt ligands and receptors. However, both use the same complex cytoneme network to disseminate and receive these signals in the tumour microenvironment. This discovery is potentially game-changing because it demonstrates the importance of the tumour cytoneme network and targeting this network could allow us to control signalling, hence tumour behaviour. In this project, the student will apply novel microfluidic tools to elucidate the exact function of Wnt cytonemes in the tumour microenvironment, specifically in gastric adenomas. Focusing on cancer- associated fibroblasts and gastric cancer cells, the student will develop a high-throughput method to screen for effective new therapeutics and characterise unknown tumour signalling properties. Concomitantly, the student will test for the function of Wnt signalling in the promotion of gastric cancer stemness, thus developing and optimising individual treatment regimes. In summary, we believe the outcomes of this project will fundamentally change our understanding of signalling in gastric cancer and provide novel and effective tools to study tumour microenvironment interactions in individual cancers.

Application details

Alumni

Dr Benjamin Matthes

Dr Daniel Routledge

Dr Joana Viana

Dr Chengting Zhang

Jenna Corcoran

Holly Elson

Simone Schindler

Collaborators

Prof Robert Kelsh, U Bath

Toby Phesse, PhD, Cardiff U

Prof Trevor Dale, Cardiff U

Prof David Virshup, Duke-NUS

Prof Selina Wray, UCL

Prof Katie Lunnon, CMH Exeter

Prof Melissa Fishel, IU, US

Prof Paul Martin, Bristol