In plain terms, the difference lies in gene regulation — which genes are active — rather than in the genes themselves. To investigate, the researchers used tumor organoids, miniature lab-grown tumors derived from mouse models of several colon cancer types and from colorectal cancer patients. Across these organoids, metastatic cells shared one key feature: activation of the YAP1 program.

What does YAP1 do?

YAP1 is a protein that partners with other factors to switch on genes involved in development, stem cell maintenance, and regeneration. In a healthy gut, it springs into action only briefly, after severe injury or infection, through a rare fetal-like cell type that rebuilds the intestinal lining.

"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. We see the tumor cells hijack this program to drive metastatic progression," says Swagata Goswami, the study's lead author.

Activating this gene set helps cancer cells break free from the original tumor and colonize distant organs. Researchers have linked YAP1 to cancer for years; the new contribution is showing that diet-derived lipids push tumor cells into this regenerative state, and that the state itself licenses metastasis.

How does a high-fat diet switch it on?

In mouse studies, cancer cells in animals fed a high-fat diet turned on YAP1 more strongly than in mice on a healthy diet. The mechanism works in steps:

• The high-fat diet activates enzymes that produce ceramides, a type of lipid.
• Ceramides release the molecular brake that normally keeps YAP1 inactive.
• Freed YAP1 moves into the cell nucleus and switches on its target genes, driving proliferation and migration.

When the researchers genetically targeted YAP1 or the ceramide-production genes, the spread of colon cancer to the liver in mice dropped markedly.

Do the findings apply to people?

To check relevance to human disease, the team analyzed RNA sequencing data — readouts of gene activity — from colorectal cancer patients. YAP1 was more active in metastatic cancer cells. Patients with higher body mass index (BMI) showed higher expression of the genes YAP1 activates, and patients with higher levels of those genes had lower survival rates.

"We don't think that the YAP1 program is specific to obesity. It's just that it becomes accentuated in obesity, and that may account for why obesity is known to drive the progression of colorectal cancer," Yilmaz says.

The team now plans to develop drugs inhibiting two ceramide-producing enzymes, DEGS1 and DEGS2, hoping to prevent colon cancer metastasis in patients.

What are the limits?

The findings are preliminary in important ways. The mechanistic results come largely from mice and organoids, not from controlled trials in people. The researchers caution that the work does not yet translate into dietary advice for diagnosed patients. Any drug targeting ceramide synthesis will also face a high bar for selectivity, because ceramides play essential roles in healthy tissues, so a drug must block the harmful activation without disrupting normal function.

The research was funded by the National Institutes of Health/National Cancer Institute, the MIT Stem Cell Initiative, a Koch Institute Frontier grant, and the NRW Junior Research Program.