Reprogramming of a melanoma genome by nuclear transplantation.
We have used nuclear transplantation to test whether the reprogramming activity of oocytes can reestablish developmental pluripotency of malignant cancer cells. We show here that the nuclei of leukemia, lymphoma, and breast cancer cells could support normal preimplantation development to the blastocyst stage but failed to produce embryonic stem (ES) cells. However, a blastocyst cloned from a RAS-inducible melanoma nucleus gave rise to ES cells with the potential to differentiate into multiple cell types in vivo including melanocytes, lymphocytes, and fibroblasts. Chimeras produced from these ES cells developed cancer with higher penetrance, shorter latency, and an expanded tumor spectrum when compared with the donor mouse model. These results demonstrate that the secondary changes of a melanoma nucleus are compatible with a broad developmental potential but predispose mice to melanomas and other malignant tumors on reactivation of RAS. Our findings serve as a paradigm for studying the tumorigenic effect of a given cancer genome in the context of a whole animal.
Hochedlinger
Konrad
K
Whitehead Institute for Biomedical Research, and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
Blelloch
Robert
R
Brennan
Cameron
C
Yamada
Yasuhiro
Y
Kim
Minjung
M
Chin
Lynda
L
Jaenisch
Rudolf
R
D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002678:Chimera; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D011905:Genes, ras; D016678:Genome; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D053652:Nuclear Transfer Techniques; D009865:Oocytes; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2