Journal Article

DKFZ-2026-02386

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Ceramide synthesis mediates colorectal cancer metastasis through a YAP-driven regenerative program.

Goswami, S. ; Zhang, Q. ; Yildiz, A. B. ; Das Adhikari, U. ; Raghawan, A. K. ; Bulliard, M. ; Sedhain, S. ; Darawshi, O. ; Celik, C. E. ; Cansiz, F.DKFZ* ; Krempe, C. P.DKFZ* ; Rösler, J.DKFZ* ; Allies, G.DKFZ* ; Meckelmann, S. W. ; Chi, C. ; Hormann, F.-L. ; Heiles, S. ; Sedlak, J. ; Grace, W. ; Eng, G. ; Reich, E. ; Alquati, C. ; Williams, K. J. ; Read, B. J. ; Rashan, E. H. ; Li, Z. ; Jnawali, A. ; Ortiz, J. A. ; Jain, C. ; Whittaker, C. A. ; Yilmaz, O. H. ; Deshpande, V. ; Schmitz, O. J. ; Sickmann, A. ; York, A. G. ; Kwon, D. S. ; Neumann, U. ; Fedorova, M. ; Vander Heiden, M. G. ; Ogretmen, B. ; Sethi, N. S. ; Tasdogan, A.DKFZ* ; Yilmaz, Ö. H.

2026
American Association for the Advancement of Science Washington, DC

Abstract: 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.

Keyword(s): Ceramides: biosynthesis (MeSH) ; Colorectal Neoplasms: pathology (MeSH) ; Colorectal Neoplasms: metabolism (MeSH) ; Animals (MeSH) ; Adaptor Proteins, Signal Transducing: metabolism (MeSH) ; YAP-Signaling Proteins (MeSH) ; Protein Phosphatase 2: metabolism (MeSH) ; Transcription Factors: metabolism (MeSH) ; Phosphoproteins: metabolism (MeSH) ; Signal Transduction (MeSH) ; Oxidoreductases: metabolism (MeSH) ; Oxidoreductases: genetics (MeSH) ; Neoplasm Metastasis (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Phosphorylation (MeSH) ; Cell Line, Tumor (MeSH) ; Cell Cycle Proteins (MeSH) ; Ceramides ; Adaptor Proteins, Signal Transducing ; YAP-Signaling Proteins ; Protein Phosphatase 2 ; Transcription Factors ; Phosphoproteins ; Oxidoreductases ; Yap1 protein, mouse ; dihydroceramide desaturase ; YAP1 protein, human ; Cell Cycle Proteins

Note: #DKTKZFB9#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 50 ; Index Chemicus ; JCR ; National-Konsortium ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

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