Cellular pathway that allows colorectal cancer to metastasize

MIT researchers identified a cellular program that may explain how colorectal cancer spreads, despite the absence of a distinctive genetic mutation separating metastatic cells from the original tumor. In tumor organoids from mouse models and patients, metastatic cells showed increased activity of YAP1, a protein that switches on genes involved in development, stem-cell maintenance, and tissue repair. The team argues that cancer cells hijack a normally temporary, injury-response state in the gut: its regenerative activity helps them multiply, leave the primary tumor, and establish growth elsewhere, most often in the liver.

Experiments in mice linked this switch to ceramides, fatty molecules whose production rises on a high-fat diet. Ceramides remove a restraint on YAP1, enabling it to enter the nucleus and activate its target genes. Disabling YAP1 or genes needed to make ceramides substantially reduced liver metastases. Analysis of patient data likewise found higher YAP1 activity in metastatic tumors; its target genes were more strongly expressed in patients with higher BMI, and high expression was associated with poorer survival. The researchers are investigating drugs that inhibit the ceramide-producing enzymes DEGS1 and DEGS2. The findings do not establish dietary guidance for people already diagnosed with cancer, and treatments would need to avoid disrupting ceramides’ essential roles in healthy tissue.