EpCAM: A multifunctional protein at the crossroads of cancer biology, diagnosis, and immunotherapy.

The cell surface protein of EpCAM (Epithelial Cell Adhesion Molecule), also known as CD326, is generally expressed in normal epithelia; whereas, its upregulation has been reported in certain tissue stem cells, precursors, and a number of epithelium-derived tumors. EpCAM was initially introduced as a transmembrane glycoprotein modulating cell-cell adhesion and facilitating epithelial-specific intercellular cell adhesion. However, its recognized functions have expanded to include diverse roles in fundamental cellular processes, such as the regulation of proliferation, differentiation, cell migration, and cell signaling. The aim of the current review is to unravel the mechanisms by which EpCAM controls the initiation of cancer through interactions and the formation of a complex with Wnt pathway molecules; also, to summarize and discuss the original data obtained from international research laboratories on the properties of EpCAM, including its expression in human CSCs (Cancer Stem Cells) and CTCs (Circulating Tumor Cells). Questions such as how this property led to this molecule being considered as a modulator of epithelial plasticity or phenotypic flexibility rather than a true structural adhesion molecule that mdiates mechanical cell-cell adhesion, are also addressed. This review provides the significance of EpCAM-based identification in liquid biopsy and describes the main complications and challenges in its clinical applications for targeted therapeutic approaches. We also discuss new insights on EpCAM-targeted therapeutic approaches, including monoclonal antibodies, CAR-T cells, and bispecific antibodies. In conclusion, we discuss future research directions in which EpCAM targeting could contribute to further progress in cancer diagnosis, prognosis, and treatment.