Swagata Goswami, Qiming Zhang, Abdullah Burak Yildiz, Upasana Das Adhikari, Akhouri Kishore Raghawan, Manon Bulliard, Sabhyata Sedhain, Odai Darawshi, Cigdem Elif Celik, Feyza Cansiz, Constantin P Krempe, Jonas Rösler, Gabriele Allies, Sven W Meckelmann, Chiashin Chi, Felix-Levin Hormann, Sven Heiles, Joseph Sedlak, Wesley Grace, George Eng, Ethan Reich, Chiara Alquati, Kevin J Williams, Benjamin J Read, Edrees H Rashan, Zhixin Li, Anup Jnawali, Jose A Ortiz, Chesta Jain, Charles A Whittaker, Osman H Yilmaz, Vikram Deshpande, Oliver J Schmitz, Albert Sickmann, Autumn G York, Douglas S Kwon, Ulf Neumann, Maria Fedorova, Matthew G Vander Heiden, Besim Ogretmen, Nilay S Sethi, Alpaslan Tasdogan, Ömer H Yilmaz
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 Degs1. 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 Basp1, that promotes metastasis. Selective elimination of Basp1high cancer cells prevented metastatic seeding. Degs1 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.