Suppression of Colon Cancer Metastasis by Aes through Inhibition of Notch Signaling

SummaryMetastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in ApcΔ716 intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis.

► Aes suppresses colon cancer metastasis in an orthotopic transplantation model
► Aes is an endogenous inhibitor of Notch signaling
► Notch signaling is activated in cancer cells by ligands on stromal cells
► Aes knockout in ApcΔ716 mice cause local invasion and intravasation of tumor cells