We have shown that
carcinoembryonic antigen cell adhesion molecule 1 long
isoform (CEACAM1-L) expression in MC38 metastatic
colorectal cancer (CRC) cells results in liver
metastasis inhibition via CCL2 and STAT3 signaling. But other molecular mechanisms orchestrating CEACAM1-L-mediated
metastasis inhibition remain to be defined. We screened a panel of mouse and human CRC cells and evaluated their metastatic outcome after
CEACAM1 overexpression or downregulation. An unbiased transcript profiling and a phospho-
receptor tyrosine kinase screen comparing MC38 CEACAM1-L-expressing and non-expressing (CT) CRC cells revealed reduced
ephrin type-A receptor 2 (EPHA2) expression and activity. An EPHA2-specific inhibitor reduced EPHA2 downstream signaling in CT cells similar to that in CEACAM1-L cells with decreased proliferation and migration. Human CRC patients exhibiting high
CEACAM1 in combination with low EPHA2 expression benefited from longer time to first recurrence/
metastasis compared to those with high EPHA2 expression. With the added interaction of CEACAM6, we denoted that
CEACAM1 high- and EPHA2 low-expressing patient samples with lower CEACAM6 expression also exhibited a longer time to first recurrence/
metastasis. In HT29 human CRC cells, down-regulation of
CEACAM1 along with CEA and CEACAM6 up-regulation led to higher metastatic burden. Overall, CEACAM1-L expression in poorly differentiated CRC can inhibit liver
metastasis through cell context-dependent EPHA2-mediated signaling. However,
CEACAM1's role should be considered in the presence of other CEACAM family members.