title: Novel function of MDA-9/Syntenin (SDCBP) as a regulator of survival and stemness in glioma stem cells.
abstract: Glioblastoma multiforme (GBM) is an aggressive cancer with current therapies only marginally impacting on patient survival. Glioma stem cells (GSCs), a subpopulation of highly tumorigenic cells, are considered major contributors to glioma progression and play seminal roles in therapy resistance, immune evasion and increased invasion. Despite clinical relevance, effective/selective therapeutic targeting strategies for GSCs do not exist, potentially due to the lack of a definitive understanding of key regulators of GSCs. Consequently, there is a pressing need to identify therapeutic targets and novel options to effectively target this therapy-resistant cell population. The precise roles of GSCs in governing GBM development, progression and prognosis are under intense scrutiny, but key upstream regulatory genes remain speculative. MDA-9/Syntenin (SDCBP), a scaffold protein, regulates tumor pathogenesis in multiple cancers. Highly aggressive cancers like GBM express elevated levels of MDA-9 and contain increased populations of GSCs. We now uncover a unique function of MDA-9 as a facilitator and determinant of glioma stemness and survival. Mechanistically, MDA-9 regulates multiple stemness genes (Nanog, Oct4 and Sox2) through activation of STAT3. MDA-9 controls survival of GSCs by activating the NOTCH1 pathway through phospho-Src and DLL1. Once activated, cleaved NOTCH1 regulates C-Myc expression through RBPJK, thereby facilitating GSC growth and proliferation. Knockdown of MDA-9 affects the NOTCH1/C-Myc and p-STAT3/Nanog pathways causing a loss of stemness and initiation of apoptosis in GSCs. Our data uncover a previously unidentified relationship between MDA-9 and GSCs, reinforcing relevance of this gene as a potential therapeutic target in GBM.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Sarmistha
authors.initials: S
authors.lastname: Talukdar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Pradhan
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Xue-Ning
authors.initials: XN
authors.lastname: Shen
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Jolene J
authors.initials: JJ
authors.lastname: Windle
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.|VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D051881:Receptor, Notch1 / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000502:physiology; D053676:Syntenins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: C436291:CDKN1B protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; C109621:SDCBP protein, human; D050796:STAT3 Transcription Factor; D053676:Syntenins; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: MDA-9/Syntenin (SDCBP); apoptosis; glioma stem cells; stemness; survival