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

J Clin Invest. 2012 Nov;122(11):4077-93. doi: 10.1172/JCI64057. Epub 2012 Oct 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / immunology*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Female
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology*
  • Homeodomain Proteins / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Nanog Homeobox Protein
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / immunology
  • Neoplastic Stem Cells / metabolism*
  • 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
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Transcription, Genetic / genetics
  • Transcription, Genetic / immunology
  • Transplantation, Heterologous
  • Tumor Escape*


  • Homeodomain Proteins
  • NANOG protein, human
  • Nanog Homeobox Protein
  • Proto-Oncogene Proteins
  • TCL1A protein, human
  • Proto-Oncogene Proteins c-akt