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 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 Basp1 high 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.
Authors
- Maria Fedorova (ORCID: https://orcid.org/0000-0002-4692-3885)
- Autumn Gabrielle York (ORCID: https://orcid.org/0000-0002-0331-043X)
- Matthew G. Vander Heiden (ORCID: https://orcid.org/0000-0002-6702-4192)
- Jonas Rösler
- Besim Öğretmen (ORCID: https://orcid.org/0000-0002-1019-5660)
- Albert Sickmann (ORCID: https://orcid.org/0000-0002-2388-5265)
- Sven Heiles (ORCID: https://orcid.org/0000-0003-3779-8071)
- Akhouri Kishore Raghawan (ORCID: https://orcid.org/0000-0002-1628-5974)
- Charles A. Whittaker (ORCID: https://orcid.org/0000-0002-2400-0094)
- Ömer H. Yilmaz (ORCID: https://orcid.org/0000-0002-7577-4612)
- Nilay S. Sethi (ORCID: https://orcid.org/0000-0002-3748-7559)
- Odai Darawshi (ORCID: https://orcid.org/0000-0003-0380-4496)
- Vikram Deshpande (ORCID: https://orcid.org/0000-0003-4230-9308)
- José Antonio Ortiz (ORCID: https://orcid.org/0000-0003-0505-3032)
- Oliver Johannes Schmitz (ORCID: https://orcid.org/0000-0003-2184-1207)
- Alpaslan Tasdogan (ORCID: https://orcid.org/0000-0003-2543-852X)
- Edrees H. Rashan (ORCID: https://orcid.org/0000-0002-3882-6655)
- George Eng (ORCID: https://orcid.org/0000-0003-0272-9623)
- Abdullah Burak Yıldız (ORCID: https://orcid.org/0000-0001-8921-2736)
- Feyza Cansiz (ORCID: https://orcid.org/0009-0006-6526-990X)
- Manon Bulliard (ORCID: https://orcid.org/0009-0009-2292-7046)
- Sven W. Meckelmann (ORCID: https://orcid.org/0000-0002-0407-7879)
- Swagata Goswami (ORCID: https://orcid.org/0000-0002-8289-2860)
- Joseph C. Sedlak (ORCID: https://orcid.org/0000-0002-7989-4515)
- Chiara Alquati (ORCID: https://orcid.org/0000-0002-2003-3622)
- Gabriele Allies (ORCID: https://orcid.org/0009-0000-0784-9021)
- Upasana Das Adhikari (ORCID: https://orcid.org/0009-0002-0782-9033)
- Benjamin J. Read (ORCID: https://orcid.org/0000-0002-4056-296X)
- Ulf P. Neumann (ORCID: https://orcid.org/0000-0002-3831-8917)
- Kevin J. Williams (ORCID: https://orcid.org/0000-0001-8091-7924)
- Douglas S. Kwon (ORCID: https://orcid.org/0000-0001-8521-8735)
- Felix-Levin Hormann (ORCID: https://orcid.org/0009-0006-3784-6124)
- Qiming Zhang (ORCID: https://orcid.org/0000-0003-4282-2996)
- Zhixin Li (ORCID: https://orcid.org/0000-0001-9962-3942)
- Osman H. Yilmaz (ORCID: https://orcid.org/0000-0001-9822-7112)
- Wesley W Grace (ORCID: https://orcid.org/0009-0000-3514-6737)
- Cigdem Elif Celik (ORCID: https://orcid.org/0000-0002-8542-9791)
- Sabhyata Sedhain
- Constantin P. Krempe (ORCID: https://orcid.org/0009-0007-1000-7408)
- Anup Jnawali
- Ethan Reich (ORCID: https://orcid.org/0009-0001-0689-6253)
- Chiashin Chi
- Chesta Jain
Institutions
- Broad Institute (US)
- Albert Einstein College of Medicine (US)
- Beth Israel Deaconess Medical Center (US)
- Harvard University (US)
- Medical University of South Carolina (US)
- University of California, Los Angeles (US)
- University of Washington (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Maastricht University (NL)
- Ege University (TR)
- Massachusetts General Hospital (US)
- MUSC Hollings Cancer Center (US)
- Hacettepe University Hospital (TR)
- Dana-Farber Cancer Institute (US)
- Essen University Hospital (DE)
- Leibniz Institute for Analytical Sciences - ISAS (DE)
- Gilead Sciences (Spain) (ES)
- Gilead Sciences (United States) (US)
- University Hospital Carl Gustav Carus (DE)
- University of Duisburg-Essen (DE)
- Massachusetts Institute of Technology (US)
- Hacettepe University (TR)
- Technische Universität Dresden (DE)
- Ruhr University Bochum (DE)
- University of Bologna (IT)
- University of California, Berkeley (US)
Publication Details
- Journal
- Science
- Published
- 2026-09-24
- DOI
- https://doi.org/10.1126/science.adw8520
- Primary Topic
- Sphingolipid Metabolism and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00