title: Nanog signaling in cancer promotes stem-like phenotype and immune evasion.
abstract: 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.
authors.affiliation: Division of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, Republic of Korea.
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Noh
authors.forename: Bo Wook
authors.initials: BW
authors.lastname: Kim
authors.forename: Kwon-Ho
authors.initials: KH
authors.lastname: Song
authors.forename: Hanbyoul
authors.initials: H
authors.lastname: Cho
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Lee
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Joon-Yong
authors.initials: JY
authors.lastname: Chung
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Seong
authors.forename: Chih-Ping
authors.initials: CP
authors.lastname: Mao
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000071317:Nanog Homeobox Protein; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic / Q000235:genetics / Q000276:immunology; D014183:Transplantation, Heterologous; D019139:Tumor Escape
chemical_list: D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; D051057:Proto-Oncogene Proteins c-akt