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Identification of therapeutic targets for glioblastoma by network analysis

Oncogene volume 35, pages 608–620 (2016)Cite this article

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Abstract

Glioblastoma can originate from terminally differentiated astrocytes and neurons, which can dedifferentiate to a stem cell-like state upon transformation. In this study, we confirmed that transformed dedifferentiated astrocytes and neurons acquired a stem/progenitor cell state, although they still retained gene expression memory from their parental cell. Transcriptional network analysis on these cells identified upregulated genes in three main pathways: Wnt signaling, cell cycle and focal adhesion with the gene Spp1, also known as osteopontin (OPN) serving as a key common node connecting these three pathways. Inhibition of OPN blocked the formation of neurospheres, affected the proliferative capacity of transformed neurons and reduced the expression levels of neural stem cell markers. Specific inhibition of OPN in both murine and human glioma tumors prolonged mice survival. We conclude that OPN is an important player in dedifferentiation of cells during tumor formation, hence its inhibition can be a therapeutic target for glioblastoma.

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Acknowledgements

We thank Gabriela Estepa for her technical help and Ruben Alvarez Rodriguez for designing the inducible miRNA lentivector. IMV is an American Cancer Society Professor of Molecular Biology, and holds the Irwin and Joan Jacobs Chair in Exemplary Life Science. This work was supported in part by grants from the NIH (HL053670) (to IM Verma and D Friedmann-Morvinski), Cancer Center Core Grant (P30 CA014195-38), the H.N. and Frances C. Berger Foundation, and the Leona M. and Harry B. Helmsley Charitable Trust grant #2012-PG-MED002 (to IM Verma). S Subramaniam is supported by National Institutes of Health (NIH) National Heart, Lung and Blood Institute Grant HL087375, HL106579, HL108735, the National Science Foundation (NSF) grants DBI-0835541 and STC-0939370. V Bhargava was the recipient of a California Institute for Regenerative Medicine (CIRM) Graduate Fellowship (T1-00003 and TG2-01154, Interdisciplinary Stem Cell Training Program at UCSD). Accession Code. Gene Expression Omnibus: GSE64411 (sequencing read data).

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Author notes

  1. D Friedmann-Morvinski and V Bhargava: Co-first authors.

  2. I M Verma and S Subramaniam: Co-senior authors.

Authors and Affiliations

  1. Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA

    D Friedmann-Morvinski & I M Verma

  2. Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    D Friedmann-Morvinski

  3. Bioinformatics and Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA, USA

    V Bhargava & S Subramaniam

  4. Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA

    S Gupta & S Subramaniam

  5. Department of Cellular and Molecular Medicine and Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA

    S Subramaniam

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Correspondence to I M Verma or S Subramaniam.

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Friedmann-Morvinski, D., Bhargava, V., Gupta, S. et al. Identification of therapeutic targets for glioblastoma by network analysis. Oncogene 35, 608–620 (2016). https://doi.org/10.1038/onc.2015.119

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