Nanog signaling in cancer promotes stem-like phenotype and immune evasion

• Published in: The Journal of clinical investigation 2012-11, Vol.122 (11), p.4077-4093
• Main Authors: Noh, Kyung Hee, Kim, Bo Wook, Song, Kwon-Ho, Cho, Hanbyoul, Lee, Young-Ho, Kim, Jin Hee, Chung, Joon-Yong, Kim, Jae-Hoon, Hewitt, Stephen M, Seong, Seung-Yong, Mao, Chih-Ping, Wu, T-C, Kim, Tae Woo
• Format: Article
• Language: English
• Subjects: Adaptations; AKT protein; Animal models; Animals; Antigens; Apoptosis; Apoptosis - genetics; Apoptosis - immunology; Biomedical research; Cancer; Cancer therapies; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cell Line, Tumor; Cell Proliferation; Cellular signal transduction; Cervical cancer; Chemotherapy; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - immunology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Evolution; Female; Flow cytometry; Genetic aspects; Genotype & phenotype; Homeodomain Proteins - genetics; Homeodomain Proteins - immunology; Homeodomain Proteins - metabolism; Identification and classification; Immunogenetics; Mice; Mice, Inbred NOD; Mice, SCID; Nanog Homeobox Protein; Neoplasm Transplantation; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - metabolism; Phenotype; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - immunology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - immunology; Proto-Oncogene Proteins c-akt - metabolism; Radiation; Signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; Transcription; Transcription, Genetic - genetics; Transcription, Genetic - immunology; Transplantation, Heterologous; Tumor cells; Tumor Escape; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci64057

Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process.