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NANOG signaling promotes metastatic capability of immunoedited tumor cells

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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.

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Abbreviations

EMT:

Epithelial-mesenchymal transition

CSC:

Cancer stem cell

CTL:

Cytotoxic T lymphocyte

TIC:

Tumor initiating cell

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Acknowledgments

This work was supported by NRF grants funded by the MEST, Republic of Korea (2012R1A6A3A010105372 2012R1A2A2A01007527 and 2013M3A9D3045881, and 2014R1A2A1A10054205), and Korea University Grant.

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No potential conflicts of interest were disclosed.

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    Authors and Affiliations

    1. Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Korea

      Hyo-Jung Lee, Kyung Hee Noh, Young-Ho Lee, Kwon-Ho Song, Se Jin Oh, So Youn Kim & Tae Woo Kim

    2. Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, Seoul, Korea

      Hyo-Jung Lee, Kyung Hee Noh, Young-Ho Lee, Kwon-Ho Song, Se Jin Oh, So Youn Kim & Tae Woo Kim

    3. Department of Biochemistry & Molecular Biology, College of Medicine, Korea University, MoonSook Medical Hall, Room319, 73 Inchon-ro, Sungbuk-gu, Seoul, 136-705, Korea

      Tae Woo Kim

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    Hyo-Jung Lee and Kyung Hee Noh have contributed equally to this work.

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    Lee, HJ., Noh, K.H., Lee, YH. et al. NANOG signaling promotes metastatic capability of immunoedited tumor cells. Clin Exp Metastasis 32, 429–439 (2015). https://doi.org/10.1007/s10585-015-9717-2

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