title: Identification of therapeutic targets for glioblastoma by network analysis.
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.
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.|Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Friedmann-Morvinski
authors.affiliation: Bioinformatics and Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Bhargava
authors.affiliation: Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Verma
authors.affiliation: Bioinformatics and Systems Biology Graduate Program, University of California at San Diego, La Jolla, CA, USA.|Department of Bioengineering, University of California at San Diego, La Jolla, CA, USA.|Department of Cellular and Molecular Medicine and Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D053495:Osteopontin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C506895:SPP1 protein, human; C506896:Spp1 protein, mouse; D053495:Osteopontin