Scientists Discover Molecular Switch Behind Colon Cancer's Spread to Liver

Scientists have identified a molecular switch that may help explain how colorectal cancer becomes more dangerous and spreads to the liver. Researchers found that when levels of the gene-regulating factor GATA6 decline, cancer cells can lose their normal identity and transform into flexible, fetal-like cells capable of travelling through the bloodstream and forming new tumours. The findings suggest that this process is driven mainly by changes in gene activity rather than new genetic mutations.

Researchers from Weill Cornell Medicine and the Massachusetts Institute of Technology found that GATA6 normally acts as an identity regulator in cells lining the intestine, helping them maintain their specialised functions. The study, published on June 22 in Cell Stem Cell, found significantly lower GATA6 levels in liver metastases from both mice and people with colorectal cancer. Reduced expression of the factor was also associated with poorer outcomes among patients.

Scientists have long searched for specific genetic mutations that cause colorectal cancer to spread to the liver, but no clear driver mutations have been identified. The latest research instead points to epigenetic changes, which influence whether genes are activated or suppressed without altering the underlying DNA sequence. According to the researchers, the loss of GATA6 acts as a critical switch that can transform cancer cells in a primary tumour from a non-metastatic state into one capable of spreading.

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To study the early stages of metastasis, the team developed laboratory models using organoids derived from liver metastases. These miniature three-dimensional clusters of cancer cells were implanted into the colons of mice, where they formed increasingly aggressive tumours that later spread to the liver. By repeating the process, researchers observed how cancer cells gradually acquired the ability to metastasise and found that the loss of GATA6 promoted greater cellular flexibility.

When GATA6 was absent, colorectal cancer cells activated alternative genetic programmes and entered a fetal-like state that made them better equipped to move through the bloodstream and establish tumours in distant organs. The researchers also observed a shift from cells carrying the intestinal stem-cell marker LGR5 to LGR5-negative cells, which previous studies have linked to liver metastasis. Restoring GATA6 activity or related pathways reduced the cancer cells' ability to spread.

The findings suggest GATA6 could eventually serve as a biomarker to identify colorectal cancer patients at greater risk of metastasis and may also offer a potential target for future treatments. Researchers said therapies could focus on preserving cancer cells' identity or preventing them from entering highly adaptable states, although such approaches must avoid interfering with normal tissue repair. Future studies will examine vulnerabilities in GATA6-deficient cancer cells and the role of immune cells and liver-specific signals in tumour spread.

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