Mice lacking a single protein in their colon tumors developed far more liver metastases than mice that kept it. The primary tumors grew at about the same pace. That contrast sits at the center of a study from Weill Cornell Medicine and the Massachusetts Institute of Technology, published June 22 in Cell Stem Cell.
The protein is GATA6. It switches genes on and off, and in the lining of the intestine it keeps cells locked into their specialized jobs. Dr. Norihiro Goto, an assistant professor of medicine at Weill Cornell who co-led the work, put the finding bluntly: “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.”
For many people with colorectal cancer, the liver is where the disease turns deadly. Doctors have hunted for years for a gene mutation that explains the jump, and none has been named as the cause. Goto’s team argues the answer may lie elsewhere. “Our findings suggest that epigenetic changes may be more important for promoting liver metastasis,” he said. Epigenetic changes alter how genes are used without altering the DNA sequence itself.
Building the spread in the lab
Studying metastasis is hard because researchers usually see tumors only after the damage is done. “When researchers analyze patient samples from liver metastases, we fail to capture the important signals occurring in the early stages of the metastatic process,” Goto said.
So the team grew organoids, small three-dimensional clusters of cancer cells, from liver metastases. They implanted these in the colons of mice, let the tumors seed the liver, and repeated the cycle. Each round selected for cells that spread more efficiently.
In both the mouse models and patient samples, GATA6 levels were much lower in liver metastases than in primary tumors. Low GATA6 also tracked with worse outcomes for patients.
A step back to a fetal state
Without GATA6, the cancer cells gave up their intestinal identity, a process called lineage plasticity. They switched on gene programs more typical of fetal development. Those fetal-like cells were more flexible and better suited to the trip from tumor to bloodstream to a new organ.
The cells also shifted from an LGR5-positive state to an LGR5-negative one. Earlier studies had shown that LGR5-negative cells are good at starting liver metastases. When the researchers silenced GATA6, more cells made that switch. Restoring GATA6 activity, or turning on related pathways, cut the cells’ 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.
What it could mean for patients
The researchers think GATA6 could work as a biomarker. Tumors with low levels may be more likely to hold cells that can turn metastatic, which might help doctors pick out patients who need closer monitoring or more aggressive treatment.
A drug is a long way off. Healthy tissue uses similar cell-reprogramming programs to repair itself after injury, so any therapy that blocks them has to avoid damaging that repair. The team’s next steps are to look for weaknesses unique to GATA6-deficient cancer cells and to test how immune cells and signals from the liver shape 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. Patients with questions about their own care should talk to their doctors.
Sources
- Scientists Uncover a Hidden Switch That Helps Colon Cancer Spread to the Liver
- Study identifies molecular switch that helps colon cancer spread to the liver
