MIT biologists have identified a YAP1-controlled cellular pathway that is essential for colorectal cancer metastasis, especially to the liver.

The same pathway shows YAP1 activates a regenerative program normally used for tissue repair, enabling cancer cells to proliferate and migrate.

This research links the metastatic ability to the activation of a regenerative program, suggesting YAP1’s role in driving spread beyond the primary tumor.

Researchers aim to develop inhibitors targeting the ceramide-synthesis enzymes DEGS1 and DEGS2 as potential therapies to prevent metastasis.

They caution that findings do not translate to dietary guidance for patients and that ceramide pathways are essential in healthy tissues, necessitating highly selective drugs.

The plan includes pursuing ceramide-synthesis inhibitors as a therapeutic strategy to block metastasis.

Dietary fat can influence metastasis by increasing ceramide production, which relieves inhibition on YAP1 and permits activation of genes that promote proliferation and migration.

A high-fat diet elevates ceramide levels, enabling YAP1 to activate its target genes and drive a regenerative state in cancer cells.

In mouse models, high-fat diet enhances YAP1 activation and ceramide production, suggesting diet-derived lipids push tumor cells toward metastasis.

Blocking ceramide production or genetically targeting YAP1 and ceramide-synthesis enzymes significantly reduces liver metastasis in mice, highlighting a druggable pathway.

Experiments show that inhibiting ceramide production or targeting YAP1 and ceramide-synthesis genes markedly lowers liver metastasis in animal models.

RNA sequencing of human colorectal cancer samples reveals higher YAP1 activity in metastatic cells, with elevated expression of YAP1-target genes correlating with higher BMI and poorer survival.