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

• Published in: Nature communications Vol. 7; no. 1; pp. 11471 - 9
• Main Authors: Miyawaki, Shingo, Kawamura, Yoshimi, Oiwa, Yuki, Shimizu, Atsushi, Hachiya, Tsuyoshi, Bono, Hidemasa, Koya, Ikuko, Okada, Yohei, Kimura, Tokuhiro, Tsuchiya, Yoshihiro, Suzuki, Sadafumi, Onishi, Nobuyuki, Kuzumaki, Naoko, Matsuzaki, Yumi, Narita, Minoru, Ikeda, Eiji, Okanoya, Kazuo, Seino, Ken-ichiro, Saya, Hideyuki, Okano, Hideyuki, Miura, Kyoko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.05.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 38/91; 631/136/532/2064/2158; 631/67/581; 692/308/2171; 692/420/755; Animals; Cancer; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - immunology; Cellular Reprogramming - genetics; Cellular Reprogramming - immunology; Cloning; Gene expression; Genes, Tumor Suppressor; Humanities and Social Sciences; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - immunology; Induced Pluripotent Stem Cells - transplantation; Life sciences; Male; Medicine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Mole Rats - genetics; Mole Rats - immunology; multidisciplinary; Mutation; Oncogene Protein p21(ras) - genetics; Oncogene Protein p21(ras) - immunology; Polymerase chain reaction; Reading Frames; Rodents; Science; Science (multidisciplinary); Senescence; Stem cells; Teratoma - genetics; Teratoma - immunology; Testicular Neoplasms - genetics; Testicular Neoplasms - immunology; Tumors; Japan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11471

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. The naked mole-rat exhibits an exceptional resistance to cancer. Here, the authors show that induced pluripotent stem cells derived from the naked mole-rat lack teratoma-forming tumorigenicity due to a naked mole-rat-specific ARF-dependent tumour-suppression mechanism.