Recreating a signalling process in the test tube provides clues to bowel cancer

Scientists have, for the first time, recreated an assembly of proteins known as the β-catenin destruction complex in the test tube. This is a long-awaited step in cancer research, as mutations in this destruction complex are found in a large percentage of bowel and other cancers.

β-catenin is constantly created and destroyed in a natural cycle, so the overall amount available in the cells is kept low. However, mutations in β-catenin itself can cause it to skip the destruction part of this cycle. Ultimately this tells the cell to keep dividing uncontrollably – which leads to cancer.

The team, led by researchers at the The Institute of Cancer Research, London, managed to recreate the β-catenin process in the test tube using purified proteins. 

This process plays a key role in coordinating cells to develop in the embryo as well as tissue maintenance and regeneration throughout adulthood.

The study, funded mainly by Cancer Research UK, with contributions from Wellcome, the Lister Institute of Preventive Medicine and the ICR itself, will help researchers pinpoint the intricate mechanisms at play in both healthy cell function and cancer.

Understanding the impact of tumour suppressors

β-catenin is involved in a variety of processes, including cell reproduction, cell maintenance, tissue organisation, and cell death – important reasons why β-catenin protein levels in the cell need to be finely balanced.

The research, which was published in the journal Molecular Cell, focusses on two tumour suppressors that are part of the destruction complex. 

One of these is adenomatous polyposis coli, or APC. Mutations in the APC gene are present in most colon cancers, but researchers do not fully understand the functions of APC yet, so it is of particular interest. 

The other is the AXIN1, also a tumour suppressor, which acts as a scaffold that holds the destruction complex together. It is also critical to degrade β-catenin. 

By reconstructing the destruction complex, the team obtained detailed insights into how these two essential tumour suppressors function in β-catenin turnover. They also looked into how this process goes awry in cancer. 

Disruptions to the process keeping β-catenin protein levels in check are one of the main causes that can lead to polyps and abnormal growths of tissue in our intestines, a common precursor to bowel cancer.

 The drug discovery tightrope walk

Discoveries like this provide potential ways to answer long-standing questions in cancer treatment, such as how we can inhibit cell signals that lead to tumour growth. 

Dr Sebastian Guettler, Deputy Head of the Division of Structural Biology at The Institute of Cancer Research, London, who led the team that carried out this research, said:

“It is one of the most prominent cancer pathways, so if we can inhibit it, this would have a strong impact. 

“However, the challenge is that many stem cells depend on this pathway and targeting oncogenic signalling without inhibiting essential stem cell functions is a real tightrope walk. 

“By learning more about the fundamental mechanisms at the core of β-catenin processing, we hope to uncover new approaches to modulate oncogenic Wnt/β-catenin signalling.”

Michael Ranes, the first author of the study and a postdoctoral fellow at the ICR, said:

“There are currently no cancer drugs in the clinic that target the Wnt/β-catenin pathway, in part because a therapeutic with this effect has the possibility of damaging healthy cells.”

The team’s research provides new insights into the precise consequences of cancer mutations in APC. This information will be vital to finding ways of reigning in oncogenic signalling without affecting normal cell growth. 

This also means that there is the potential to examine how the destruction complex responds to different pharmacological strategies and, just as importantly, ascertain why they do or don’t work.

Five years in the making

This long-awaited achievement provides a new ‘tool’ in the cancer research toolbox; this advance has very much been catalysed by recent technological developments.

Dr. Guettler added: “Rebuilding the destruction complex from purified proteins was a big technical challenge and therefore took nearly five years of research to realise.

 “I am really very grateful to the ICR, its supporters, and our funders, for taking a risk with us because this sort of work can only pay off if we are given the freedom to pursue long-term projects.”

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