MIT biologists have identified a cellular pathway that enables colorectal cancer to colonise distant organs. The study, published in Science, was led by senior authors Omer Yilmaz of the MIT Stem Cell Initiative and the Koch Institute, Nilay Sethi of Harvard Medical School and Dana-Farber, and Alpaslan Tasdogan of University Hospital Essen. Growing tumour organoids from mouse models and from patients, the team found that metastatic cells consistently switch on YAP1, a programme that normally drives tissue repair after injury.
The lipid connection proved decisive. In mice, a high-fat diet activated YAP1 more strongly through ceramide lipids, which release the protein from its usual inhibition, while genetically disabling YAP1 or the ceramide-producing genes markedly reduced spread to the liver. Analysis of patient RNA sequencing data pointed the same way: metastatic cells showed higher YAP1 activity, and patients with elevated body mass index or raised YAP1 target genes had poorer survival.
The clinical stakes are high, since up to a third of patients with stage 2 or 3 colon cancer relapse with metastatic disease after surgery. The researchers now plan to develop selective inhibitors of the ceramide enzymes DEGS1 and DEGS2 as a route to preventing metastasis, while cautioning that the findings do not yet translate into dietary advice for people already diagnosed.