Scientists have identified a molecular switch that explains why colorectal cancer becomes more deadly. When levels of the gene-regulating factor GATA6 decline, cancer cells lose their normal identity and transform into highly adaptable, fetal-like cells that can spread through the bloodstream and form new tumours in the liver, according to a study published June 22 in Cell Stem Cell.
The research, led by Dr. Norihiro Goto, assistant professor of medicine at Weill Cornell Medicine, and Dr. Omer H. Yilmaz, associate professor of biology at the Massachusetts Institute of Technology, suggests that this transition is driven primarily by epigenetic changes—how genes are activated or suppressed—rather than by new genetic mutations.
GATA6 Acts as an 'Identity Keeper'
GATA6 normally serves as a molecular "identity keeper" in cells lining the intestine, helping them maintain specialised functions. However, the study found that GATA6 levels are much lower in liver metastases from both mice and colorectal cancer patients. 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 epigenetic mechanisms. "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. "Our findings suggest that epigenetic changes may be more important for promoting liver metastasis."
Organoid Models Reveal Metastatic Transition
To study early metastatic events, the team developed organoids—three-dimensional clusters of cancer cells—from liver metastases. They implanted these organoids into mouse colons, generating aggressive tumours that spread to the liver. Repeating this process allowed observation of how cancer cells gradually acquire metastatic abilities.
The experiments revealed that GATA6 loss promotes lineage plasticity, enabling cells to alter their identity and behavior. Without GATA6, 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 tumours in distant organs. This cellular reshaping normally occurs during wound repair and stress adaptation, but in cancer, it drives metastasis.
GATA6 Loss Creates Cells Primed for Liver Metastasis
One sign of this plasticity was the appearance of cells lacking LGR5, a marker of intestinal stem cells. Earlier research showed 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 to an LGR5-negative state, displaying fetal-like characteristics and metastatic ability. Restoring GATA6 activity or activating related pathways reduced metastatic potential.
"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, also a member of the Jill Roberts Institute and the Sandra and Edward Meyer Cancer Center at Weill Cornell. The findings suggest that metastasis may depend more on specific transitions between cellular states than on primary tumor growth rate or size.
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 therapeutic strategy focused on maintaining cellular identity or preventing cancer cells from entering pro-metastatic states. However, Dr. Norihiro Goto noted that researchers must 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 and investigating how the tumor microenvironment influences these transitions.
