Dr Luke Boulter: Role of Wnt in fibrosis in PSC

The role of non-canonical Wnt signalling in the establishment of fibrosis during PSC

PSC Support-funded research update from Dr Luke Boulter

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 PSC Support grant awarded was £18,106.13

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 is 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.  

(Dr Luke Boulter 20 April 2017)