Nanog signaling in cancer promotes stem-like phenotype and immune evasion
Kyung Hee Noh, … , T.-C. Wu, Tae Woo Kim
Kyung Hee Noh, … , T.-C. Wu, Tae Woo Kim
Published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4077-4093. https://doi.org/10.1172/JCI64057.
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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

Kyung Hee Noh, Bo Wook Kim, Kwon-Ho Song, Hanbyoul Cho, Young-Ho Lee, Jin Hee Kim, Joon-Yong Chung, Jae-Hoon Kim, Stephen M. Hewitt, Seung-Yong Seong, Chih-Ping Mao, T.-C. Wu, Tae Woo Kim

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Figure 3

Nanog promotes the stem-like and immune-resistant phenotype of tumor cells through the Akt pathway.

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Nanog promotes the stem-like and immune-resistant phenotype of tumor cel...
(A–C) Western blot analysis of expression and activation status (A) of a panel of major signaling molecules in P0 or P3 cells or (B) of Nanog and pAkt expression in P3 cells treated with siGFP or siNanog or (C) in empty vector– or Nanog cDNA–transfected P0 cells. β-Actin was included as an internal loading control. (D and G) Western blot analysis of pAkt or total Akt levels in Nanog-transfected P0 cells treated with either (D) API2 and DMSO control or (G) siAKT and siGFP control. (E and H) Sphere-forming capacity of Nanog-transfected P0 cells treated with either (E) API2 and DMSO control or (H) siAKT and siGFP control. Original magnification, ×40. (F and I) Flow cytometry analysis of the frequency of apoptotic (active caspase-3+) cells in Nanog-transfected P0 cells treated with either (F) API2 and DMSO control or (I) siAKT and siGFP control after incubation with E7-specific CTLs at a 1:1 ratio for 4 hours (isotype control staining is indicated by solid gray region; anti-active caspase-3 staining is indicated by black lines). (A–D and G) Numbers below blots indicate expression as measured by fold change. Error bars represent mean ± SD.