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Sox2 is required for tumor development and cancer cell proliferation in osteosarcoma

Oncogene volume 37, pages 4626–4632 (2018)Cite this article

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Abstract

The stem cell transcription factor Sox2 is highly expressed in many cancers where it is thought to mark cancer stem cells (CSCs). In osteosarcomas, the most common bone malignancy, high Sox2 expression marks and maintains a fraction of tumor-initiating cells that show all the properties of CSC. Knockdown of Sox2 expression abolishes tumorigenicity and suppresses the CSC phenotype. Here we show that, in a mouse model of osteosarcoma, osteoblast-specific Sox2 conditional knockout (CKO) causes a drastic reduction in the frequency and onset of tumors. The rare tumors detected in the Sox2 CKO animals were all Sox2 positive, indicating that they arose from cells that had escaped Sox2 deletion. Furthermore, Sox2 inactivation in cultured osteosarcoma cells by CRISPR/CAS technology leads to a loss of viability and proliferation of the entire cell population. Inactivation of the YAP gene, a major Hippo pathway effector which is a direct Sox2 target, causes similar results and YAP overexpression rescues cells from the lethality caused by Sox2 inactivation. These effects were osteosarcoma-specific, suggesting a mechanism of cell “addiction” to Sox2-initiated pathways. The requirement of Sox2 for osteosarcoma formation as well as for the survival of the tumor cells suggests that disruption of Sox2-initiated pathways could be an effective strategy for the treatment of osteosarcoma.

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Acknowledgements

This investigation was supported by NYSTEM contract CO29560 and NIH/ NCI-R21CA186031. We thank Dr. Stuart Orkin for providing us with the Tp53, Rb mutant mice; Matthew Murtha for his contribution to some of the initial experiments; and Upal BasuRoy for helpful discussions. We also wish to acknowledge the Histopathology core services at NYU Langone Medical Center.

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  1. These authors contributed equally: Giulia Maurizi, Narendra Verma.

Authors and Affiliations

  1. Department of Microbiology, NYU School of Medicine, New York, NY, 10016, USA

    Giulia Maurizi, Narendra Verma, Abhilash Gadi, Alka Mansukhani & Claudio Basilico

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  1. Giulia Maurizi
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  2. Narendra Verma
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  3. Abhilash Gadi
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Correspondence to Alka Mansukhani or Claudio Basilico.

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Maurizi, G., Verma, N., Gadi, A. et al. Sox2 is required for tumor development and cancer cell proliferation in osteosarcoma. Oncogene 37, 4626–4632 (2018). https://doi.org/10.1038/s41388-018-0292-2

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