Anti-CEACAM5 monoclonal antibody, clone 2216

The discovery of the carcinoembryonic antigen (CEA) as a tumor marker for colorectal cancer some 50 years ago became the first step in the identification of a much larger family of 12 carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) with surprisingly diverse functions in cell adhesion, in intracellular and intercellular signaling, and during complex biological processes such as cancer progression, inflammation, angiogenesis, and metastasis. The development of proper molecular and biochemical tools and mouse models has enabled bidirectional translation of the CEACAM network biology. Indeed, CEACAM1, CEACAM5, and CEACAM6 are now considered valid clinical biomarkers and promising therapeutic targets in melanoma, lung, colorectal, and pancreatic cancers. These fascinating proteins illustrate how a better understanding of the CEACAM family of cell adhesion molecules reveals their functional link to the underlying disease and lead to new monitoring and targeting opportunities.

Emerging evidence supports the hypothesis that multicellular tumor clusters invade and seed metastasis. However, whether tumor-associated stroma induces epithelial-mesenchymal plasticity in tumor cell clusters, to promote invasion and metastasis, remains unknown. We demonstrate herein that carcinoma-associated fibroblasts (CAFs) frequently present in tumor stroma drive the formation of tumor cell clusters composed of two distinct cancer cell populations, one in a highly epithelial (E-cadherin(hi)ZEB1(lo/neg):E-hi) state and another in a hybrid epithelial/mesenchymal (E-cadherin(lo)ZEB1(hi):E/M) state. The E-hi cells highly express oncogenic cell-cell adhesion molecules, such as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 that associate with E-cadherin, resulting in increased tumor cell cluster formation and metastatic seeding. The E/M cells also retain associations with Ehi cells, which follow the E/M cells leading to collective invasion. CAF-produced stromal cell-derived factor 1 and transforming growth factor-beta confer the Ehi and E/M states as well as invasive and metastatic traits via Src activation in apposed human breast tumor cells. Taken together, these findings indicate that invasive and metastatic tumor cell clusters are induced by CAFs via epithelial-mesenchymal plasticity.