title: NANOG signaling promotes metastatic capability of immunoedited tumor cells.
abstract: Metastatic recurrence after cancer treatments with radiation, cancer drugs, or even immunotherapeutic agents (cytokine, antibody, lymphocyte etc.) is often intractable and fatal for cancer patients. Therefore, molecular understanding of metastatic recurrence is necessary. Recently, these recurrent and metastatic tumor cells with resistance to cancer drugs have been reported to possess stem-like attributes and epithelial-mesenchymal transition (EMT) phenotype. Previously, we also found that antigen-specific cytotoxic T lymphocyte (CTL)-mediated immunotherapy conferred tumor cells with immune-resistant and stem-like phenotypes by hyper-activating NANOG/TCL1/AKT signaling axis. In this study, we report that these immunoedited cells have high metastatic capability and phenotypes. These cells exhibit enhanced migration, infiltration, and invasiveness in vitro as well as formation of metastatic lung nodules in vivo. Moreover, they display EMT-like features characterized by increased expression of BMI1 and TWIST1. Importantly, these pleiotropic phenotypes of metastasis through the expression of the EMT-associated molecules were critically dependent on the NANOG/TCL1A/AKT signaling axis, which was also conserved across multiple types of human cancer. Thus, we provide proof of the principle that inhibition of the NANOG axis is an effective strategy to control metastasis of immunoedited cancer, particularly, after CTL-based immunotherapy.
authors.affiliation: Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea.
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Noh
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Kwon-Ho
authors.initials: KH
authors.lastname: Song
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Oh
authors.forename: So Youn
authors.initials: SY
authors.lastname: Kim
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051879:Twist-Related Protein 1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C069077:BMI1 protein, human; D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C090851:TCL1A protein, human; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D063150:Polycomb Repressive Complex 1; D051057:Proto-Oncogene Proteins c-akt