Dr Boulter - Non-canonical Wnt signalling
The role of non-canonical Wnt signalling in the establishment of fibrosis during PSC
Awarded to University of Edinburgh
Dr Luke Boulter, Leverhulme Trust- Chancellor's Fellow, Tissue Growth and Cancer Group Leader, MRC Human Genetics Unit, Edinburgh
The total grant awarded is £18,106.13
Duration of award: 11 May 2015 to 11 May 2016
Award details: The role of non-canonical Wnt signalling in the establishment of fibrosis during PSC
Primary Sclerosing Cholangitis (PSC) is a chronic liver disease in which the bile ducts, tubes which drain bile from the liver into the intestine, become damaged and forms scar tissue. Over time this scarring affects the function of the liver. A great deal of work has been done looking at how the liver scars following viral infection or alcoholism; by comparison the processes by which the bile ducts scar is relatively understudied. There is currently no treatment for PSC and end-stage disease can only be treated with a liver transplant, in which PSC reoccurs in one-third of patients following transplantation. Furthermore patients with PSC have a highly increased chance of developing bile duct cancer, which has a very poor prognosis. Recently we have identified a molecule called Van Gogh-like 2 (Vangl2) which is not widely present in the healthy liver, but is switched on very quickly in a mouse model of PSC. In this study we will ask the question is Vangl2 needed to start PSC and ask how it does this in order to look for drugs which could inhibit this pathway.
In PSC many different types of liver cells are needed to cause bile duct scarring. However, how these cells communicate to each other is not understood. By finding out how these cells talk with one another, we might be able to interfere with this communication and improve the liver’s function by preventing the liver forming scar tissue.
In this study, we found that macrophages, cells which are normally responsible for repairing injury and staving off infection, come in close contact to bile ducts and produce a signal known as Wnt. We have been able to show that the activity of this Wnt signal in bile ducts causes them to talk to another type of cell, known as a fibroblast. The job of fibroblasts in the liver is to make scar tissue. These cells are important and when you have a cut, for example, and you need to quickly close the cut, scarring is a good thing. However in PSC, lots of scar tissue is produced when it doesn’t need to be and this leads to fibrosis near the bile ducts. We have been able to show that one of the ways too much scar tissue made is caused by Wnt. We have been able to use a drug, which blocks Wnt, and show that this halves the amount of fibrosis in a mouse with PSC.
Another line of our work funded by the AMMF and Cancer Research UK has been to look at what Wnt does in cholangiocarcinoma, a cancer of the bile duct. Using the same drugs as we have used in a mouse with PSC, we have found that these drugs can reduce the number of cholangiocarcinoma that form in the liver and it also shrinks cholangiocarcinoma.
One question we still have is can we use our Wnt blocking drug to reduce the chances of cholangiocarcinoma forming in patients with PSC, as currently, we have only tested our Wnt blocking drug once cancer has formed. Following-on from the funding from PSC Support, we have applied to the Medical Research Council to continue this research and to determine whether using these drugs will be widely applicable in PSC patients and patients with cholangiocarcinoma. (April 2017)
Impact of this study
As well as this publication (below) demonstrating that Wnt regulates bile duct scarring, a Master's thesis (for Mr David Wilson) was successfully submitted on the back of this study.
It also led to funding from Cancer Research UK (£1.5M) to continue work on studying how the microenvironment regulates cholangiocytes in pre-malignant disease and cancer, particularly looking at the interface between the two. (August 2021)