Tumour resistance in induced pluripotent stem cells derived from naked mole-rats

Nat Commun. 2016 May 10;7:11471. doi: 10.1038/ncomms11471.

Abstract

The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype-ARF suppression-induced senescence (ASIS)-that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Cellular Reprogramming / genetics
  • Cellular Reprogramming / immunology
  • Genes, Tumor Suppressor*
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / immunology*
  • Induced Pluripotent Stem Cells / transplantation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Mole Rats / genetics*
  • Mole Rats / immunology*
  • Mutation
  • Oncogene Protein p21(ras) / genetics
  • Oncogene Protein p21(ras) / immunology
  • Reading Frames
  • Teratoma / genetics
  • Teratoma / immunology
  • Testicular Neoplasms / genetics
  • Testicular Neoplasms / immunology

Substances

  • Oncogene Protein p21(ras)