Researchers at Weill Cornell Medicine and the Massachusetts Institute of Technology think they have found a reason colorectal cancer so often reaches the liver. The answer, reported June 22 in Cell Stem Cell, is not a new mutation. It is a protein that goes missing.
The protein is GATA6, a transcription factor, which means it helps decide which genes a cell switches on or off. In the cells lining the intestine it acts as a molecular “identity keeper,” holding them to their specialized jobs. When GATA6 levels drop, cancer cells lose that identity and turn into flexible, fetal-like cells. Those cells can travel through the bloodstream and seed new tumors in the liver.
The team found GATA6 much lower in liver metastases from both mice and people with colorectal cancer. Lower expression also went along with poorer outcomes for patients. Once the disease leaves its original site, treatment gets far harder, and metastasis remains the leading cause of death from colorectal cancer.
For years, researchers hunted for genetic mutations that might set off liver metastasis. No clear driver mutations ever surfaced. Dr. Norihiro Goto, an assistant professor of medicine in gastroenterology and hepatology at Weill Cornell, who co-led the work, described what his group saw instead.
“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,” he said. “Our findings suggest that epigenetic changes may be more important for promoting liver metastasis.”
Mutations rewrite the DNA sequence itself. Epigenetic changes leave the sequence alone and alter which genes are active, and so which proteins a cell makes. Dr. Saori Goto, an instructor in medicine at Weill Cornell, was first author. Dr. Omer H. Yilmaz, an associate professor of biology at MIT, co-led the study.
A model built to catch the early steps
Norihiro Goto said samples from established liver metastases give only a late snapshot. “When researchers analyze patient samples from liver metastases, we fail to capture the important signals occurring in the early stages of the metastatic process,” he said.
So his team grew organoids from liver metastases. These are tiny three-dimensional clusters of cancer cells that copy many features of real tumors. The scientists implanted them in the colons of mice, where they formed more aggressive tumors that spread to the liver. After several rounds, the team could watch cancer cells pick up the ability to metastasize.
Losing GATA6 promoted what scientists call lineage plasticity, a cell’s capacity to change its identity and behavior. Cells without GATA6 switched on other gene programs. The body normally uses this kind of reshaping to heal wounds and cope with stress, and here it may drive metastasis instead.
One sign was the appearance of cells lacking LGR5, a marker found on intestinal stem cells. Earlier work had shown that LGR5-negative cells can start liver metastases. Shutting down GATA6 moved cancer cells from LGR5-positive to LGR5-negative, and restoring GATA6, or activating related pathways, reduced their ability to spread.
“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,” Goto said. The researchers read that as a sign metastasis hinges on shifts between cell states more than on how fast or how large a primary tumor grows.
What could come next
The findings raise the possibility of using GATA6 as a biomarker for metastatic risk. Tumors low in the protein may be more likely to hold cells able to flip into the pro-metastatic state. That could help doctors pick out patients who need closer monitoring or more aggressive treatment.
A treatment might also aim to preserve cellular identity or stop cancer cells entering those flexible states. Goto noted the hard part: any approach must avoid interfering with normal tissue repair, which uses similar programs.
Next, the team plans to look for weaknesses specific to GATA6-deficient cancer cells and to test how immune cells and liver-specific signals in the tumor microenvironment affect these 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.”
Patients with questions about colorectal cancer should consult their doctor.
Sources
- Scientists discover how colon cancer cells change identity to spread
- New Genetic Discovery Explains Why Colorectal Cancer Spreads so Quickly
- Colon cancer cells may change identity to metastasize | Cornell Chronicle
