LAUSR

Elevated levels of the carcinoembryonic antigen (CEA; CEACAM5) in the serum of colorectal cancer (CRC) patients represent a clinical biomarker that correlates with disease recurrence. However, a mechanistic role for soluble CEA (sCEA) in tumor progression and metastasis remains to be established. In our study, we report that sCEA acts as a paracrine factor, activating human fibroblasts by signaling through both the STAT3 and AKT1‐mTORC1 pathways, promoting their transition to a cancer‐associated fibroblast (CaF) phenotype. sCEA‐activated fibroblasts express and secrete higher levels of fibronectin, including cellular EDA+‐fibronectin (Fn‐EDA) that selectively promote the implantation and adherence of CEA‐expressing cancer cells. Immunohistochemical analyses of liver tissues derived from CRC patients with elevated levels of sCEA reveal that the expression of cellular Fn‐EDA co‐registers with CEA‐expressing liver metastases. Taken together, these findings indicate a direct role for sCEA as a human fibroblast activation factor, in priming target tissues for the engraftment of CEA‐expressing cancer cells, through the differentiation of tissue‐resident fibroblasts, resulting in a local change in composition of the extracellular matrix.