Most deaths from colorectal cancer are caused by tumor cells spreading, most often to the liver. MIT biologists identified a cellular pathway controlled by the protein YAP1 that is required for metastasis. In normal tissue YAP1 participates in fetal development and injury repair; when activated it promotes proliferation and migration.
Using mouse tumor organoids and patient‑derived organoids, the researchers found that metastatic cells consistently up‑regulate the YAP1 program. A high‑fat diet increases synthesis of ceramides, which releases the brake on YAP1, allowing it to enter the nucleus and activate a regenerative gene set. Genetic deletion of YAP1 or pharmacological inhibition of the ceramide‑producing enzymes DEGS1 and DEGS2 markedly reduced liver metastasis in mice.
Analysis of human RNA‑seq data showed higher YAP1 activity in metastatic samples, and patients with higher BMI exhibited stronger expression of YAP1 target genes and poorer survival. The team now aims to develop DEGS1/DEGS2 inhibitors as a potential strategy to prevent colorectal cancer metastasis.
Review