Identification of a potential therapeutic target in colorectal cancer initiation

Tumour in mouse intestinal epithelium
Tumour in mouse intestinal epithelium

Colorectal cancer is one of the most common cancers in the UK. Virtually all colorectal cancers are initiated by hyperactive signalling through the Wnt/β-catenin pathway. This can occur due to activating mutations in the protein β-catenin or inactivation of Adenomatous Polyposis Coli (APC), a protein that normally drives degradation of β-catenin. Mariann Bienz’s group from the LMB’s PNAC Division, in collaboration with Doug Winton at the Cancer Research UK Cambridge Institute, have identified a potential new colorectal cancer therapeutic target in this signalling pathway.

The Wnt signalling pathway is an ancient cell communication system that controls the embryonic development of tissues and organs in all animals by turning a range of genes on or off. Importantly, Wnt signalling is also active in the stem cells found in most tissues in adult animals. Control of Wnt signalling in the adult stem cells in our bodies allows the appropriate proliferation required to replace cells that are ordinarily lost, such as blood cells or the cells lining the intestine. It is thought that hyperactive Wnt signalling enables a differentiated intestinal epithelial cell to revert back into a stem cell-like state to become a cancer stem cell, driving inappropriate cell proliferation and tumour formation.

Familial Adenomatous Polyposis (FAP) patients inherit an inactivating mutation in one of their copies of APC. Loss of the second copy is then sufficient to allow tumour formation and, in this way, patients with this disease develop thousands of benign tumours in their colon in their teenage years. By the age of 40, one of these benign tumours is bound to progress to become cancerous. Sporadic or spontaneous colorectal cancer, in which the patient has no known genetic mutation making tumourigenesis more likely, develops similarly, but at a slower rate. Scientists wanting to study colorectal cancer have developed mouse models carrying Apc-inactivating mutations that drive tumourigenesis similarly to FAP.

Wnt-directed transcriptional regulation relies on a multi-protein complex called the Wnt enhanceosome. Previously, Mariann’s group had identified the proteins BCL9 and Pygo as integral components of the Wnt enhanceosome in flies and human cells, and now aimed to investigate their role in intestinal tumourigenesis. Juliusz Mieszczanek, Laurens Moore van Tienen, and Ashraf Ibrahim, from Mariann’s group, showed that loss of both Bcl9 and Pygo together synergises to shift cells in benign FAP-like tumours from stem cell-like to differentiated gene expression. They also found that deletion of Bcl9 and Pygo extends disease-free survival in mice with Apc-inactivating mutations. Perhaps their most significant result was that loss of Bcl9 alone essentially cured a mouse model, recently developed by Ian Tomlinson’s group at the University of Oxford, and restored a normal lifespan in these otherwise very sick mice. In this model, tumour formation is driven by the most common APC mutation found in human colorectal cancers, which underscores the significance of Mariann’s study for the human disease.

This work demonstrates a key role of the Wnt enhanceosome in β-catenin-dependent intestinal tumourigenesis and identifies BCL9 as a potential therapeutic target during the early stages of colorectal cancer. With colorectal cancer being the second most common cause of cancer mortality in the developed world, identifying drug targets that could be beneficial to patients is of great importance. This is of particular interest since the Wnt pathway is perhaps the only well-established cancer pathway for which therapeutics have not yet been developed. Indeed, β-catenin is thought to be undruggable, but this study opens up new avenues for targeting its interaction with BCL9.

This work was funded by the MRC and Cancer Research UK.

Further references

Bcl9 and Pygo synergise downstream of Apc to effect intestinal neoplasia in FAP mouse models. Mieszczanek, J., van Tienen, LM., Ibrahim, AEK., Winton, DJ., Bienz, M. Nature Communications 10:724
Mariann Bienz’s group page
Doug Winton’s group page
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