Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program.

Mechanisms by which primary tumor cells acquire metastatic capability through metabolic and signaling adaptations are currently poorly understood. We demonstrate that tumor-intrinsic ceramide metabolism, amplified by dietary fat, initiates colorectal cancer metastasis. We observed that dietary fat exposure triggers a sustained increase in de novo ceramide biosynthesis, mediated by the dihydroceramide desaturase . Ceramide accumulation activates yes-associated protein (YAP) through protein phosphatase 2A (PP2A)-mediated dephosphorylation, promoting a durable shift toward a distinct YAP-driven regenerative (YAP-DR) program, marked by , that promotes metastasis. Selective elimination of cancer cells prevented metastatic seeding. loss reduced ceramide levels, YAP activity, YAP-DR signatures, and metastasis without affecting primary tumor growth, whereas blocking ceramide degradation enhanced YAP activity and metastasis. These findings identify ceramide-induced YAP signaling as a key mediator of metastatic initiation, operating independently of primary tumor expansion.