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

Oncogene volume 32, pages 2249–2260 (2013)Cite this article

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Abstract

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.

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Acknowledgements

We would like to thank: Timothy C Wang MD for critical discussions and manuscript review; Sara Siddiqi and Gannie Tzonove for general technical assistance; Carlos Cordo-Cardo MD PhD for assistance with solid tumor pathological review and discussion; Benjamin Tycko MD PhD for assistance with DNA methylation analysis; Bachir Alobeid MD for assistance with hematological pathological review; Pavel Sumazin PhD for bioniformatic analysis. IM receives funding from NCI, Gerstner CDA and the Damon Runyon Cancer Research Fund.

Author contributions: XZ performed all experiments and assisted with experimental design. MT assisted with experiments and data interpretation. FDC assisted with experiments and data interpretation. FR reviewed and interpreted all histopathology outlined. IM designed the concept and experiments, interpreted the data and wrote the manuscript. IM receives funding from NCI, Gerstner CDA and the Damon Runyon Cancer Research Fund.

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Authors and Affiliations

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

    X Zhang, F D Cruz, M Terry, F Remotti & I Matushansky

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Correspondence to I Matushansky.

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Zhang, X., Cruz, F., Terry, M. et al. Terminal differentiation and loss of tumorigenicity of human cancers via pluripotency-based reprogramming. Oncogene 32, 2249–2260 (2013). https://doi.org/10.1038/onc.2012.237

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  • DOI: https://doi.org/10.1038/onc.2012.237

Keywords

  • sarcoma
  • stem cells
  • induced pluripotent stem cells

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