Intracellular domain of epithelial cell adhesion molecule induces Wnt receptor transcription to promote colorectal cancer progression
- Author：Sushree Shankar Panda, Chi‑Chiu Lee, Khamushavalli Geevimaan, Kai‑Chi Chen, Shung‑Haur Yang , Chia‑Ning Shen, Wei‑Chun HuangFu and Han‑Chung Wu
- Journal： Journal of Biomedical Science https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-024-01057-y
Epithelial cell adhesion molecule (EpCAM) is known to widely be expressed in varieties of solid tumors and tumor-initiating cells thereby fuelling cancer progression via participating in several critical signaling pathways. Such participation distinctly include the extracellular (EpEX) as well as the intracellular (EpICD) domains of the protein. A recent study by Prof Han-Chung Wu’s group report that EpICD functions as a transcriptional co-factor for the receptors of Wnt signaling, a key pathway involved in multitudes of cancer-associated functionalities including colorectal cancer (CRC) pathogenesis. In addition, the authors further show that a humanized form of EpCAM neutralizing antibody hEpAb2-6 successfully blocks EpICD-mediated Wnt receptor expression establishing a possible therapeutics for the treatment of colorectal cancer.
Previous studies show that Wnt signaling is critical in CRC progression wherein higher Wnt receptor expressions have been associated with robust Wnt activity. In this study, Prof Wu’s group in collaboration with Prof Chia-Ning Shen’s group from Genomics Research Center (GRC), Academia Sinica use CRC patient derived organoids (PDOs), xenografts (PDX) and various CRC cell line derived xenografts to show EpICD actively interacts with the promoters of Wnt receptors (FZD6 and LRP5/6) upregulating there transcription therefore promoting Wnt activity. In addition, activation of Wnt signaling induces cleavage activity of metalloprotease γ-secretase in order to augment further shedding of EpICD, establishing a positive-feedback-loop. In this line, hEpAb2-6 treatment attenuates shedding of EpICD increasing its membrane accumulation therefore blocking corresponding nuclear translocation. As a results, hEpAb2-6 successfully decreases the expressions of the Wnt receptors impeding the signaling processing. Thus, the antibody potentiates therapeutic benefit in various PDX and othotopic models of human CRC increasing the overall survivals of the animals.
Whilst the study highlights the mechanistic insights of EpICD mediated Wnt receptor expression, it establishes the relevant efficacies of hEpAb2-6 as a potential therapeutic antibody for the treatment of CRC. The study was published in the Journal of Biomedical Science, with Sushree Shankar Panda as the lead author and was highlighted in the STEMCELL Science News.