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Metastatic cancer stem cells (mCSCs) have been shown to be essential seeds initiating a cancer metastasis.However,the biology of mCSCs is still poorly understood.We herein used a lymph node metastatic CEA-producing GI-carcinoma cell line, UP-LN1, characterized by its persistent appearance of adherent (A) and floating (F) cells in culture passages,to determine which cell subset would be the major niche for CSCs and the induction mechanisms of mCSCs from CSCs.F and A cells exhibited distinct phenotypes, CD44high/CD24dim and CD44dim/CD24high, respectively.F cells invariably showed greater expression of multiple drug resistance genes, and about 8-fold higher frequency of tumorinitiating cells in NOD/SCID mice, compared with A cells.Moreover, F cells exhibited extreme resistance to NK/LAKmediated cytolysis, and were highly sensitive to IFN-γ-induction of enhanced surface CXCR4 expression with decrease in cytoplasmic CXCL12 expression..These latter two parameters were essentially found unchanged in NK/LAKsensitive A cells.Following the induction of CXCR4, enhanced migratory/invasive potential was demonstrated in F cells by in vitro assays.In this model, we also investigated the effect of a plant withanolide, Withaferin A (WFA), on UP-LN 1 cells.Results showed that WFA preferentially suppressed the side population cell percentage of F cells, and attenuated F cell migratory/invasive potential induced by IFN-γvia the IFN-γsignaling pathway.Taken together,our results point to the notions that the major niche of CSCs is in the F cells, and that differential immunomodulatory roles of the F and A subsets may play in tumor progression of this cell line.Our findings with this model also reinforce the concept of a critical role for the CXCL12/CXCR4 axis in invasion and metastasis, and offer a definitive preclinical validation of CXCR4 as a therapeutic target in this type of GI-malignancy.An improved understanding of the signaling pathway(s) and associated molecules that drive GI-cancer growth and progression is needed for continued advances in therapeutic development and optimization.