Study identifies molecular switch that helps colon cancer spread to the liver

Scientists have uncovered a key molecular mechanism that may explain how colorectal cancer becomes far more dangerous by spreading to the liver. A new study has found that the loss of a gene-regulating factor called GATA6 allows cancer cells to abandon their normal identity, transform into a more flexible, fetal-like state and acquire the ability to metastasise. The findings, published in Cell Stem Cell, could pave the way for new diagnostic tools and therapies aimed at preventing the deadliest stage of the disease.

How does the loss of GATA6 make colon cancer more aggressive?

Researchers from Weill Cornell Medicine and the Massachusetts Institute of Technology found that GATA6 functions as a molecular "identity keeper" in the cells lining the intestine, ensuring they retain their specialised characteristics. However, the team discovered that GATA6 levels were significantly lower in liver metastases from both mice and patients with colorectal cancer.

The study also linked reduced GATA6 expression with poorer patient outcomes. While scientists have long searched for genetic mutations responsible for liver metastasis, the new findings suggest that changes in gene activity, rather than changes in DNA itself, may play the dominant role.

"We discovered that GATA6 loss acts as a critical switch that can change cancer cells in the primary tumor from non-metastatic to pro-metastatic," said Dr. Norihiro Goto, assistant professor of medicine in the Division of Gastroenterology & Hepatology at Weill Cornell, who co-led the research.

"Our findings suggest that epigenetic changes may be more important for promoting liver metastasis," added Goto.

Unlike genetic mutations, epigenetic changes determine which genes are switched on or off, influencing how cells behave without altering the underlying DNA sequence.

The research was first authored by Dr. Saori Goto, instructor in medicine at Weill Cornell, while Dr. Omer H. Yilmaz, associate professor of biology at the Massachusetts Institute of Technology, also co-led the study.

How did researchers track the earliest stages of metastasis?

To better understand how colorectal cancer cells acquire the ability to spread, the scientists developed laboratory-grown organoids—miniature three-dimensional clusters of cancer cells derived from liver metastases.

These organoids were implanted into the colons of mice, where they developed into progressively more aggressive tumours that eventually spread to the liver. By repeating this process multiple times, the researchers were able to observe the earliest biological changes that enable metastasis.

"When researchers analyse patient samples from liver metastases, we fail to capture the important signals occurring in the early stages of the metastatic process," said Dr. Norihiro Goto.

The experiments showed that the loss of GATA6 promotes "lineage plasticity"—the ability of cells to change their identity. Without GATA6, colorectal cancer cells activated alternative genetic programmes, adopted a fetal-like state and became better equipped to travel through the bloodstream and establish tumours in distant organs.

The researchers also found that GATA6 loss caused cancer cells to transition from an LGR5-positive state to an LGR5-negative state. Previous studies have shown that LGR5-negative cells are capable of initiating liver metastases.

"When we genetically delete GATA6, the frequency and burden of liver metastases in mouse models significantly increase, while having little effect on primary tumor growth," said Dr. Norihiro Goto, who is also a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Sandra and Edward Meyer Cancer Center at Weill Cornell.

The findings suggest that the ability of cancer cells to switch identities may be more important for metastasis than the size or growth rate of the primary tumour.

Could GATA6 become a biomarker and treatment target?

The researchers believe GATA6 could serve as a biomarker to identify colorectal cancer patients at greater risk of developing liver metastases. Tumours with low GATA6 levels may be more likely to contain cells capable of transitioning into highly metastatic forms, allowing clinicians to identify high-risk patients earlier.

The study also points to the possibility of developing therapies that preserve the normal identity of cancer cells or prevent them from entering these highly adaptable, metastasis-promoting states. However, researchers caution that any such treatments must avoid disrupting normal tissue repair, which relies on similar biological mechanisms.

Future research will focus on identifying weaknesses unique to GATA6-deficient cancer cells and understanding how immune cells and the liver's microenvironment influence these cellular transitions, potentially opening new avenues for therapies aimed at preventing colorectal cancer from spreading.

(With inputs from ANI)