Fresh insights reveal how cancer gene mutations drive tumour growth
Scientists have created a comprehensive map showing how hundreds of possible mutations in a key cancer gene influence tumour growth, offering a new insight that could guide the development of more personalised treatments.
The study is co-led by Degron Cluster’s Andrew Wood and colleagues from UMC Leiden and Koç University and published in Nature Genetics. It represents a systematic genetic dissection of one of the most important natural degron peptides in the mammalian proteome – a short protein sequence encoded in exon 3 of the CTNNB1 gene that normally tags the β-catenin protein for destruction when it is no longer needed. This degron controls the canonical Wnt signalling pathway, which regulates tissue growth and repair. Because this region is a frequent hotspot for cancer-associated mutations, disruption of this molecular ‘destruction tag’ leads to β-catenin accumulation and activation of genes that drive tumour growth – a hallmark of cancer.
The research aligns closely with a paper published just weeks earlier by Alex Raven and Owen Sansom examining the same gene, reflecting growing momentum in understanding the role of CTNNB1 in cancer development.
Degron reporters drive new discoveries
By systematically testing all 342 possible single amino acid changes in the CTNNB1 mutation hotspot, the research team has created the most complete picture yet of how different mutations affect cancer behaviour. Using CRISPR-based saturation genome editing combined with a fluorescent reporter assay – a cell-autonomous system that glows in response to β-catenin activity – they measured how strongly each mutation activates the pathway. Remarkably, findings from this in vitro genetic screen were able to predict tumour–immune interactions in human liver cancer patients.
Dr Andrew Wood, Reader and Chancellor’s Fellow at the University of Edinburgh’s Institute of Genetics and Cancer, leads the Degron Cluster of the MRC National Mouse Genetics Network. This work fits squarely within the Cluster’s focus on fluorescent reporters as central experimental tools to quantify degron activity and understand protein regulation in disease.
Mouse models support human-relevant discoveries without in vivo experiments
Crucially, no new animal experiments were conducted for this study, as the work relied on primary mouse embryonic stem cells derived from a transgenic reporter mouse line previously developed by Kat Hadjantonakis at Memorial Sloan Kettering Cancer Center. The team chose mouse ES cells because they are relatively straightforward to engineer and possess an intact canonical Wnt pathway, which is highly conserved between mouse and human; the relevant protein sequence in exon 3 is 100% identical between the two species.
This approach proved remarkably successful: the outputs from the mouse cell screen accurately predicted clinically relevant phenotypes in human tumour cohorts. The findings not only support the clinical relevance of mouse-based systems, but also demonstrate how existing transgenic resources can enable impactful research without requiring additional in vivo work.
Professor Owen Sansom, Director of the MRC National Mouse Genetics Network and Director of the Cancer Research UK Scotland Institute, said: “The Network operates as an ecosystem that encourages researchers to use the best model for the scientific question at hand. This study is an excellent example of how drawing on all available resources – including previously generated mouse models – can produce clinically relevant results that will ultimately improve patient outcomes.”
Technologies enabling comprehensive analysis
The research combined several sophisticated technologies. Advanced RNA sequencing measured gene expression changes, whilst flow cytometry was used to sort millions of cells based on pathway activity levels. The team also drew on large-scale patient genomic data from cancer databases, including TCGA and COSMIC, to validate their laboratory findings across thousands of human tumours.
Key findings with clinical implications
The results revealed striking variation in mutation effects. When compared with patient data, the team discovered that different cancer types select for mutations that produce distinct levels of pathway activation.
In liver cancer specifically, two major groups of tumours emerged: those with weaker CTNNB1 mutations contained more immune cells, whilst those with stronger mutations contained fewer. This finding suggests that mutation strength may influence how tumours interact with the immune system – and potentially how they respond to immunotherapy.
Dr Wood said: “The new map provides a powerful tool for predicting how specific CTNNB1 mutations affect cancer behaviour and could support the development of more personalised treatments. As the first study to experimentally test every possible mutation in this critical hotspot, it gives scientists a clearer picture of how β-catenin drives tumour growth across different cancer types.”