TY - JOUR
T1 - NANOG signaling promotes metastatic capability of immunoedited tumor cells
AU - Lee, Hyo Jung
AU - Noh, Kyung Hee
AU - Lee, Young Ho
AU - Song, Kwon Ho
AU - Oh, Se Jin
AU - Kim, So Youn
AU - Kim, Tae Woo
N1 - Publisher Copyright:
© 2015, Springer Science+Business Media Dordrecht.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2015/6/10
Y1 - 2015/6/10
N2 - 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.
AB - 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.
KW - EMT
KW - Immunoedited cancer
KW - Metastasis
KW - NANOG
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U2 - 10.1007/s10585-015-9717-2
DO - 10.1007/s10585-015-9717-2
M3 - Article
C2 - 25899063
AN - SCOPUS:84930572335
VL - 32
SP - 429
EP - 439
JO - Clinical and Experimental Metastasis
JF - Clinical and Experimental Metastasis
SN - 0262-0898
IS - 5
ER -