Abstract Introduction: Recent studies have shown that intra-tumor heterogeneity is the main cause of therapeutic resistance in cancer. Tumor tissue is composed of heterogeneous cellular populations with a hierarchical organization governed by stem/progenitor-like cells, also referred to as cancer stem-like cells (CSCs). Epithelial cell adhesion molecule (EpCAM), also known as CD326, is over-expressed ubiquitously in CSCs that originate from epithelial lesions. Prostate cancer stem-like cells highly express EpCAM. However, little is known about how EpCAM is involved in the ability of cells to adapt to micro-environmental changes in available growth factors, which is one of the essential biological phenotypes of CSCs. Methods: EpCAM-high and EpCAM-low subpopulations of cells were established from the prostate cancer cell line PC-3. Signal transduction in response to serum starvation, signaling pathways essential for tumorigenic potential in vivo, and the machinery of serum depletion-induced dormancy and plasticity were analyzed by immunoblot, quantitative RT-PCR, flow cytometry, and immunohistochemical staining. Results: EpCAM-high and EpCAM-low PC-3 subpopulations showed markedly different responses to serum starvation. EpCAM expression was positively correlated with activation of the mammalian target of rapamycin (mTOR) and epithelial growth factor receptor (EGFR) signaling pathways. Contrary to accepted wisdom, AMP-activated protein kinase (AMPK) was gradually de-activated in EpCAM-low PC-3 cells in the absence of serum. In addition, the Spearman's rank correlation between EpCAM and LAT1 in parental, EpCAM-high, and EpCAM-low PC-3 cells was very high (0.859), which implied that the expression of EpCAM correlates with the potential of leucine uptake. Both EpCAM-high and EpCAM-low PC-3 cells exhibited tumorigenic potential, which depended on mTOR and canonical Wnt signaling, respectively. Finally, serum starvation promoted cell cycle arrest and the acquisition of a quiescent phenotype. It has been well established that there are two major mechanisms that promote G0 entry; the SCF (Fbw7)-c-Myc axis and the Skp2-p27 axis. EpCAM-high PC-3 cancer cells entered the G0 phase via the SCF (Fbw7)-c-Myc axis, while EpCAM-low cells did so via the Skp2-p27 axis. EGF-induced plasticity in EpCAM-high PC-3 cells but not in EpCAM-low PC-3 cells implies that EGFR signaling is likely to be involved in cell cycle re-entry in EpCAM-high PC-3 cells. Discussion: EpCAM regulates the AMPK signaling pathway, which is essential for the response to growth factors, characterized by EGF, in the tumor microenvironment. Furthermore, EpCAM enhances the ability of cells to enter the G0 phase under long-term serum starvation and promotes cell cycle re-entry from this dormancy upon exposure to growth factors. Taken together, these data suggest that “stemness,” including sensitivity to growth factors and plasticity between dormancy and proliferation, is maintained and regulated by EpCAM. Significance: The phenotypes induced by EpCAM expression are mainly responsible for the persistence of minimal residual disease (MRD) and the latent relapse of prostate cancers. Therefore, EpCAM may be a promising therapeutic target to block the ability of prostate cancer CSCs to adapt to the lack of growth factors in the tumor microenvironment.