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Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas

Oncogene volume 31, pages 2270–2282 (2012)Cite this article

Abstract

Tumors are thought to be sustained by a reservoir of self-renewing cells, termed tumor-initiating cells or cancer stem cells. Osteosarcomas are high-grade sarcomas derived from osteoblast progenitor cells and are the most common pediatric bone malignancy. In this report we show that the stem cell transcription factor Sox2 is highly expressed in human and murine osteosarcoma (mOS) cell lines as well as in the tumor samples. Osteosarcoma cells have increased ability to grow in suspension as osteospheres, that are greatly enriched in expression of Sox2 and the stem cell marker, Sca-1. Depletion of Sox2 by short-hairpin RNAs in independent mOS-derived cells drastically reduces their transformed properties in vitro and their ability to form tumors. Sox2-depleted osteosarcoma cells can no longer form osteospheres and differentiate into mature osteoblasts. Concomitantly, they exhibit decreased Sca-1 expression and upregulation of the Wnt signaling pathway. Thus, despite other mutations, these cells maintain a requirement for Sox2 for tumorigenicity. Our data indicate that Sox2 is required for osteosarcoma cell self renewal, and that Sox2 antagonizes the pro-differentiation Wnt pathway that can in turn reduce Sox2 expression. These studies define Sox2 as a survival factor and a novel biomarker of self renewal in osteosarcomas, and support a tumor suppressive role for the Wnt pathway in tumors of mesenchymal origin. Our findings could provide the basis for novel therapeutic strategies based on inhibiting Sox2 or enhancing Wnt signaling for the treatment of osteosarcomas.

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Acknowledgements

We thank Dr E De Stanchina (Antitumor Assessment Facility, Memorial Sloan Kettering Cancer Center, New York, NY) for excellent services and advice with the xenograft assays. Thanks to Dr J Durbin, NYU TABS, for help with tissue acquisition. This investigation was supported by PHS Grants AR051358 from the NIAMS and DE013745 from the NIDCR, and by an NCI UO1 award (to SHO). UBR is a recipient of a fellowship from The Children's Cancer Research Fund in memory of Dr A Rausen. AM is a recipient of a research grant from St Baldrick's Foundation. JAP is a postdoctoral fellow of the American Cancer Society. SHO is an Investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Department of Microbiology, New York University School of Medicine, New York, NY, USA

    U Basu-Roy, E Seo, A Mansukhani & C Basilico

  2. NYU College of Dentistry, New York, NY, USA

    L Ramanathapuram

  3. Department of Orthopedic Surgery, New York University School of Medicine, New York, NY, USA

    T B Rapp

  4. Division of Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA, USA

    J A Perry & S H Orkin

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  1. U Basu-Roy
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Correspondence to A Mansukhani or C Basilico.

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Basu-Roy, U., Seo, E., Ramanathapuram, L. et al. Sox2 maintains self renewal of tumor-initiating cells in osteosarcomas. Oncogene 31, 2270–2282 (2012). https://doi.org/10.1038/onc.2011.405

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