Scientists discover how colon cancer cells change identity to spread

GATA6 normally serves as a molecular "identity keeper" in the cells that line the intestine, helping them maintain their specialized functions. However, the study, published June 22 in Cell Stem Cell, found that GATA6 levels are much lower in liver metastases from both mice and people with colorectal cancer. The researchers also found that reduced GATA6 expression is associated with poorer patient outcomes. Once colorectal cancer spreads beyond its original site, treatment becomes far more challenging, and metastasis remains the leading cause of death from the disease.

For years, scientists have searched for genetic mutations that might trigger liver metastasis, but no clear driver mutations have emerged. Instead, the new study points to a different mechanism.

"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."

Unlike genetic mutations, which alter the DNA sequence itself, epigenetic changes influence which genes are active or inactive and therefore which proteins cells produce. Dr. Saori Goto, an instructor in medicine at Weill Cornell, served as first author of the study. Dr. Omer H. Yilmaz, associate professor of biology at the Massachusetts Institute of Technology, also co-led the work.

Organoid Models Reveal How Cancer Cells Become Metastatic

According to Dr. Norihiro Goto, studying tissue samples taken from established liver metastases provides only a limited view of the metastatic process.

"When researchers analyze 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.

To better understand those early events, the research team developed a laboratory model using organoids derived from liver metastases. These miniature, three-dimensional clusters of cancer cells reproduce many characteristics of real tumors. The scientists implanted the organoids into the colons of mice, where they formed increasingly aggressive tumors that later spread to the liver. Repeating this process several times allowed the team to observe how cancer cells gradually acquire metastatic abilities.

Their experiments revealed that the loss of GATA6 promotes lineage plasticity, which is the ability of cells to alter their identity and behavior. When GATA6 was absent, colorectal cancer cells activated alternative genetic programs and adopted a flexible fetal-like state. These transformed cells were better equipped to travel through the bloodstream and establish tumors in distant organs.

This type of cellular reshaping is normally used by the body during wound repair and adaptation to stress. In cancer, however, the same process may help drive metastasis.

GATA6 Loss Creates Cells Primed for Liver Metastasis

One sign of this plasticity was the appearance of cells lacking LGR5, a marker commonly found in intestinal stem cells. Earlier research has shown that LGR5-negative cells can initiate liver metastases.

The new study demonstrated that shutting down GATA6 causes cancer cells to shift from an LGR5-positive state to an LGR5-negative state. These cells display fetal-like characteristics and possess the ability to spread to other organs. In contrast, restoring GATA6 activity, or activating related pathways, reduced the metastatic potential of colorectal cancer cells.

"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 Jill Roberts Institute for Research in Inflammatory Bowel Disease and Sandra and Edward Meyer Cancer Center, both at Weill Cornell.

Based on these findings, the researchers suggest that metastasis may depend more on specific transitions between cellular states than on how quickly a primary tumor grows or how large it becomes.

Potential Biomarker and Future Treatment Target

The findings raise the possibility that GATA6 could serve as a biomarker for metastatic risk. Tumors with low GATA6 levels may be more likely to contain cells capable of switching into a metastasis-promoting state. Such information could help doctors identify patients who may benefit from closer monitoring or more aggressive treatment.

The study also points toward a potential therapeutic strategy focused on maintaining cellular identity or preventing cancer cells from entering highly flexible, pro-metastatic states. However, Dr. Norihiro Goto noted that researchers will need to find ways to target these processes without interfering with normal tissue repair, which relies on similar biological programs.

Future research will focus on identifying vulnerabilities unique to GATA6-deficient cancer cells that could be exploited by new therapies. The team also plans to investigate how the tumor microenvironment, including immune cells and liver-specific signals, influences these cellular transitions in preclinical models.

"In addition to treating primary tumors, we need to find strategies to target the mechanism of liver metastasis," Dr. Norihiro Goto said. "Our study is a step toward developing therapies that block the spread of cancer at the earliest stages."

This research was supported in part by the Astellas Foundation; Research Abroad from Japan Society for the Promotion of Science; the National Institutes of Health (grants R00AG076987, 01CA254314,5U01CA25055, R01CA258523, R01CA25723, R01DK133919, R01DK140310, R01CA299955, and 3OT2CA297570); Pew-Stewart Trust; AFAR and Glenn Foundation for Medical Research Breakthroughs in Gerontology; Kenneth Rainin Foundation; Crohn's & Colitis Foundation and Mark Foundation for Cancer Research.