title: CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells.
abstract: Glioblastoma (GBM) is one of the most aggressive types of cancer with limited therapeutic options and unfavorable prognosis. Stemness and non-classical epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from normal to neoplastic states as well as resistance of tumor clones to current therapies. Therefore, identification of ligand/receptor systems maintaining this privileged state is needed to devise efficient cancer therapies. In this study, we show that the expression of CD95 associates with stemness and EMT features in GBM tumors and cells and serves as a prognostic biomarker. CD95 expression increases in tumors and with tumor relapse as compared with non-tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death domain is required for maintenance of EMT-related transcripts. A combination of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically abrogates tumor sphere formation. This study molecularly dissects the role of CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM therapy.
authors.affiliation: Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Drachsler
authors.affiliation: Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kleber
authors.affiliation: Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Mateos
authors.affiliation: Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Volk
authors.affiliation: Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Mohr
authors.affiliation: Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Cell Differentiation and Tumorigenesis, Max Delbrück Center, Berlin 13125, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Cirovic
authors.affiliation: Department of Neurosurgery, Clinical Center Idar-Oberstein, Idar-Oberstein 55743, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Tüttenberg
authors.affiliation: Apogenix GmbH, Heidelberg 69120, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Gieffers
authors.affiliation: Apogenix GmbH, Heidelberg 69120, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sykora
authors.affiliation: Department of Neurosurgery, University Hospital Ulm, Günzburg 89312, Germany.
authors.forename: C R
authors.initials: CR
authors.lastname: Wirtz
authors.affiliation: Department of Neuropathology, University Hospital Leipzig, Leipzig 04103, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Mueller
authors.affiliation: Department of Neurosurgery, Charité, University Medicine Berlin, Berlin 13353, Germany.|Department of Neurosurgery, Campus Kiel, Kiel 24105, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Synowitz
authors.affiliation: Department of Molecular Neurobiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
authors.forename: A
authors.identifier: 0000-0002-9405-8910
authors.initials: A
authors.lastname: Martin-Villalba
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001932:Brain Neoplasms / Q000145:classification / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000145:classification / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D009364:Neoplasm Recurrence, Local / Q000145:classification / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis; D000077204:Temozolomide; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004338:Drug Combinations; C491901:FAS protein, human; D007074:Immunoglobulin G; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D003606:Dacarbazine; D058543:Class Ia Phosphatidylinositol 3-Kinase; C574675:APG101; D000077204:Temozolomide