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Original Article

Oncogene advance online publication 9 July 2012; doi: 10.1038/onc.2012.237

Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming

X Zhang1, F D Cruz1, M Terry1, F Remotti1 and I Matushansky1

1Division of Medical Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA

Correspondence: I Matushansky, Division of Medical Oncology, Department of Medicine, Columbia University Medical Center, 1130 St. Nicholas Ave Rm 208C, New York, NY 10032, USA. E-mail: im17@columbia.edu

Received 21 February 2012; Revised 30 April 2012; Accepted 10 May 2012
Advance online publication 9 July 2012

Pluripotent cells can be derived from various types of somatic cells by nuclear reprogramming using defined transcription factors. It is, however, unclear whether human cancer cells can be similarly reprogrammed and subsequently terminally differentiated with abrogation of tumorigenicity. Here, using sarcomas we show that human-derived complex karyotype solid tumors: (1) can be reprogrammed into a pluripotent-like state as defined by all in vitro criteria used to define pluripotent stem cells generated from somatic cells; (2) can be terminally differentiated into mature connective tissue and red blood cells; and (3) terminal differentiation is accompanied with loss of both proliferation and tumorigenicity. We go on to perform the first global DNA promoter methylation and gene expression analyses comparing human cancers to their reprogrammed counterparts and report that reprogramming/differentiation results in significant epigenetic remodeling of oncogenes and tumor suppressors, while not significantly altering the differentiation status of the reprogrammed cancer cells, in essence dedifferentiating them to a state slightly before the mesenchymal stem cell differentiation stage. Our data demonstrate that direct nuclear reprogramming can restore terminal differentiation potential to human-derived cancer cells, with simultaneous loss of tumorigenicity, without the need to revert to an embryonic state. We anticipate that our models would serve as a starting point to more fully assess how nuclear reprogramming overcomes the multitude of genetic and epigenetic aberrancies inherent in human cancers to restore normal terminal differentiation pathways. Finally, these findings suggest that nuclear reprogramming may be a broadly applicable therapeutic strategy for the treatment of cancer.
Keywords:

sarcoma; stem cells; induced pluripotent stem cells
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Source:
http://www.nature.com/onc/journal/vaop/ncurrent/abs/onc2012237a.html