Researchers at the Massachusetts Institute of Technology (MIT) have identified a biological pathway through which a high-fat diet may help colorectal cancer spread to other organs, offering a potential target for drugs designed to prevent metastasis.

The study, published in the journal Science on Sept. 24, found that dietary fat can increase the production of ceramides, a type of lipid that activates the YAP1 protein and triggers a tissue-repair program that cancer cells can exploit to spread.

Experiments in mice showed that disrupting this pathway significantly reduced the spread of colon cancer to the liver, suggesting that targeting ceramide production could offer a new approach to preventing metastatic disease. The findings have not yet been validated in clinical trials involving human patients.

Colorectal cancer often becomes life-threatening when malignant cells spread beyond the original tumor to distant organs, particularly the liver and lungs. Some patients experience metastatic recurrence even after surgery has successfully removed the primary tumor, highlighting the need for treatments that prevent cancer from spreading.

Researchers have long investigated the genetic changes that enable tumors to metastasize. The MIT study suggests that changes in gene activity and cellular metabolism, rather than additional genetic mutations alone, may help drive this process.

“Many studies have looked for a genetic driver of metastasis and come up empty,” said Omer Yilmaz, an MIT professor of biology and director of the MIT Stem Cell Initiative.

He said the absence of a distinct mutational signature separating metastatic cells from primary tumors points to the importance of changes in how genes are switched on and off.

Cancer cells exploit the body's tissue-repair mechanism

The researchers found that YAP1, a protein involved in regulating gene activity, was more active in metastatic colorectal cancer cells. Under normal conditions, YAP1 helps regulate development, stem cell maintenance and tissue regeneration following injury.

In the intestine, this regenerative response helps repair damaged tissue. However, the researchers found that cancer cells can reactivate the same program, adopting characteristics that enable them to multiply, detach from the original tumor and establish themselves in other organs.

“The regenerative program that we described is generally observed in the gut when there is severe injury or infection and the gut needs to regenerate,” said Swagata Goswami, an MIT postdoctoral researcher and co-lead author of the study.

“We see the tumor cells hijack this program to drive metastatic progression,” she added.

The team studied three-dimensional tumor models grown from patient samples, alongside mouse models of colorectal cancer. Across these models, metastatic cells showed activation of the YAP1-driven regenerative program.

The findings indicate that cancer cells may acquire the ability to spread by repurposing biological mechanisms normally used for healing, rather than relying exclusively on new mutations.

How dietary fat activates the pathway

The study identified ceramides as a key link between dietary fat and the activation of YAP1.

In mice fed a high-fat diet, the researchers observed increased activity in enzymes responsible for producing ceramides. The resulting accumulation of these lipids activated a signaling mechanism that released a molecular restraint on YAP1, allowing the protein to enter the cell nucleus and activate genes associated with regeneration and metastasis.

The researchers also analyzed gene-activity data from patients with colorectal cancer. They found that YAP1-related genes were more highly expressed in patients with higher body mass indexes, and that greater activity of these genes was associated with lower survival rates.

However, the researchers cautioned against interpreting the findings as evidence that the pathway operates exclusively in people with obesity.

“We don’t think that the YAP1 program is specific to obesity. It’s just that it becomes accentuated in obesity,” Yilmaz said.

The findings provide a possible biological explanation for the established association between obesity and colorectal cancer outcomes, although further research is needed to determine how directly the mechanism affects disease progression in humans.

Blocking ceramide production reduced metastasis in mice

In experiments, genetically disrupting YAP1 or genes involved in ceramide production substantially reduced the spread of colon cancer to the liver in mice.

The researchers found that reducing the activity of DEGS1, an enzyme involved in ceramide synthesis, lowered ceramide levels, suppressed YAP1 signaling and reduced metastatic spread without significantly affecting the growth of the primary tumor.

The results suggest that the pathway could be targeted specifically to prevent cancer cells from establishing tumors in distant organs.

“We’ve found a pathway that we think is druggable,” Yilmaz said. He added that blocking ceramide-producing enzymes prevented tumor cells from activating the regenerative program and substantially reduced their ability to seed liver metastases in the experimental models.

The team plans to investigate drugs that inhibit DEGS1 and DEGS2, two enzymes involved in ceramide production. Any potential treatment would need to target the cancer-related pathway without disrupting ceramides' essential functions in healthy tissues.

What the findings mean for patients

The research adds to a growing body of evidence linking obesity and metabolic processes to cancer biology. The US National Cancer Institute identifies obesity as a risk factor for colorectal cancer and notes that excess body weight may influence cancer development through mechanisms including inflammation and changes in insulin-related signaling.

Nevertheless, the MIT findings remain at the preclinical stage. The experiments do not establish that a high-fat diet will cause an existing human tumor to metastasize, nor do they demonstrate that reducing dietary fat or taking a drug that blocks ceramide production will prevent recurrence in patients.

Researchers are also investigating whether dietary interventions could help reduce the risk of colorectal cancer recurrence after surgery. For example, a US National Cancer Institute-listed clinical trial has examined a standardized low-fat, high-fiber diet in patients undergoing colorectal cancer surgery. Such research is separate from the MIT study and does not yet establish that a particular diet prevents metastasis.

The MIT team hopes that a better understanding of the relationship between dietary lipids, YAP1 signaling and tissue regeneration will eventually lead to therapies that prevent metastatic spread, one of the major challenges in treating colorectal cancer. (ILKHA)