Colon cancer cells may change identity to metastasize

by Weill Cornell Medical College

edited by Lisa Lock, reviewed by Andrew Zinin

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Loss of GATA6—a transcription factor that controls which genes are turned on or off—can reprogram colorectal cancer cells into more primitive, adaptable states that can then spread to the liver and establish new tumors, according to Weill Cornell Medicine and Massachusetts Institute of Technology (MIT) researchers. Understanding how cancer cells acquire the ability to metastasize could reveal new ways to stop this deadly process.

Under normal conditions, GATA6 acts like a molecular "identity keeper" for cells lining the intestine, helping maintain a stable, well-defined state. However, the study, published in Cell Stem Cell, found that GATA6 expression is significantly reduced in liver metastases in both mice and human colorectal cancer patients and that low GATA6 levels correlate with poorer clinical outcomes. Colorectal cancer becomes much more difficult to treat once it metastasizes, which is the leading cause of death.

Many studies have searched for genetic mutations that trigger liver metastasis, but driver mutations have not been found. "We discovered that GATA6 loss acts as a critical switch that can change cancer cells in the primary tumor from nonmetastatic to prometastatic," said Dr. Norihiro Goto, assistant professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell, who co-led the research. "Our findings suggest that epigenetic changes may be more important for promoting liver metastasis." While genetic mutations change the actual DNA sequence, epigenetic changes turn genes on or off, determining which proteins are made.

"As a surgeon, I cared for many patients who lost their lives to multiple liver metastases, which motivated my interest in understanding how they develop," said Dr. Saori Goto, an instructor in medicine at Weill Cornell and the study's first author. "I am excited that our findings bring us closer to unraveling the underlying mechanisms and, hopefully, to improving outcomes for patients."

Dr. Omer H. Yilmaz, associate professor of biology at the Koch Institute for Integrative Cancer Research, MIT, co-led this research.

Organoid models reveal how cancer cells evolve

"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 Goto. To address this issue, his team developed an innovative laboratory model by growing liver metastasis-derived organoids—miniature, three-dimensional clusters of cancer cells that mimic many features of tumors. They transplanted these organoids back into the colons of mice, which created more aggressive tumors that metastasized to the liver. Several rounds of this process revealed how cancer cells evolve and gain the ability to spread.

The researchers discovered that GATA6 loss in colorectal cancer cells induced lineage plasticity, a cell's ability to change its identity and behavior. As a result, tumor cells adopted alternative gene programs that transformed them into flexible, fetal-like cells capable of traveling through the bloodstream and colonizing distant organs. Usually, the body uses this cellular shapeshifting process to heal wounds or adapt to stress, but in this case, it may promote metastasis.

One hallmark of this plasticity is the emergence of cells that lack the intestinal stem cell marker LGR5. Previous studies have shown that LGR5-negative cells can initiate liver metastases. The researchers demonstrated that silencing GATA6 triggers cancer cells to switch from LGR5-positive to LGR5-negative, which have fetal-like signatures and the ability to metastasize. Conversely, restoring GATA6—or activating related molecular pathways—could decrease colorectal cancer cells' ability to metastasize.

"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 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, both at Weill Cornell. The researchers propose that metastasis is driven by specific cell-state transitions rather than by tumor size or growth rate.

Next steps

This research suggests GATA6 could serve as a biomarker for metastatic risk. Tumors with low GATA6 may be more likely to harbor cells capable of switching to a prometastatic state, which could help identify patients needing closer surveillance and more aggressive treatment.

The work also highlights a potential therapeutic approach that stabilizes cell identity or prevents cancer cells from entering flexible, prometastatic states. The challenge will be targeting plasticity therapeutically without disrupting tissue repair processes, which rely on similar programs, Goto said.

Future studies will aim to identify weaknesses unique to GATA6-deficient cancer cells that could be targeted with new therapies. The researchers will also explore how the tumor microenvironment, including interactions with immune cells and liver-specific signals, may influence cell transitions in preclinical models.

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

Publication details

Saori Goto et al, Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis, Cell Stem Cell (2026). DOI: 10.1016/j.stem.2026.05.013

Journal information: Cell Stem Cell

Key medical concepts

Colorectal CancerMetastatic Malignant Neoplasm in the LiverLGR5 Gene

Clinical categories

OncologyGastroenterology Provided by Weill Cornell Medical College Who's behind this story?

Lisa Lock

BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021. Full profile →

Andrew Zinin

Master's in physics with research experience. Long-time science news enthusiast. Plays key role in Science X's editorial success. Full profile →

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