title: A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells.
abstract: Glioblastomas are the most common primary brain tumors, highly vascularized, infiltrating, and resistant to current therapies. This cancer leads to a fatal outcome in less than 18 months. The aggressive behavior of glioblastomas, including resistance to current treatments and tumor recurrence, has been attributed to glioma stemlike/progenitor cells. The transcription factor EGR1 (early growth response 1), a member of a zinc finger transcription factor family, has been described as tumor suppressor in gliomas when ectopically overexpressed. Although EGR1 expression in human glioblastomas has been associated with patient survival, its precise location in tumor territories as well as its contribution to glioblastoma progression remain elusive. In the present study, we show that EGR1-expressing cells are more frequent in high grade gliomas where the nuclear expression of EGR1 is restricted to proliferating/progenitor cells. We show in primary cultures of glioma stemlike cells that EGR1 contributes to stemness marker expression and proliferation by orchestrating a PDGFA-dependent growth-stimulatory loop. In addition, we demonstrate that EGR1 acts as a positive regulator of several important genes, including SHH, GLI1, GLI2, and PDGFA, previously linked to the maintenance and proliferation of glioma stemlike cells.
authors.affiliation: From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Sakakini
authors.affiliation: From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Turchi
authors.affiliation: INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Bergon
authors.affiliation: INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Holota
authors.affiliation: From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France.
authors.forename: Samah
authors.initials: S
authors.lastname: Rekima
authors.affiliation: INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Lopez
authors.affiliation: From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France.
authors.forename: Philipe
authors.initials: P
authors.lastname: Paquis
authors.affiliation: From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Almairac
authors.affiliation: the Service de Neurchirurgie, Hôpital Pasteur, CHU de Nice, Nice 06107, France.
authors.forename: Denys
authors.initials: D
authors.lastname: Fontaine
authors.affiliation: Aix Marseille Université, Faculté de Médecine de la Timone, 13284 Marseille, France, CRO2, INSERM UMR 911, 13284 Marseille Cedex, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Baeza-Kallee
authors.affiliation: From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France.
authors.forename: Ellen
authors.initials: E
authors.lastname: Van Obberghen-Schilling
authors.affiliation: CNRS UMR8246 Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, INSERM U1130, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, and University Pierre and Marie Curie UMCR18, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Junier
authors.affiliation: CNRS UMR8246 Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, INSERM U1130, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France, and University Pierre and Marie Curie UMCR18, Neuroscience Paris Seine-IBPS, Team Glial Plasticity, 7 Quai Saint-Bernard, Paris 75005, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.affiliation: Aix Marseille Université, Faculté de Médecine de la Timone, 13284 Marseille, France, CRO2, INSERM UMR 911, 13284 Marseille Cedex, France, the Departement de Pathology, CHU de la Timone, 13385 Marseille Cedex 5, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, the Service d'Anatomopathologie, Hôpital Pasteur, CHU de Nice, Nice 06107, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Burel-Vandenbos
authors.affiliation: INSERM, U1090, Transcriptomic and Genomic Marseille-Luminy/Technical Advances for Genomics and Clinics (TGML/TAGC), Marseille F-13009, France, UMR_S 1090, TGML/TAGC, Aix-Marseille Université, Marseille F-13009, France, jean.imbert@inserm.fr.
authors.forename: Jean
authors.initials: J
authors.lastname: Imbert
authors.affiliation: From the Université Nice Sophia Antipolis, CNRS, INSERM, iBV, 06108 Nice, France, virolle@unice.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Virolle
mesh_terms: D019898:Autocrine Communication; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D009363:Neoplasm Proteins; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A
keywords: cancer biology; cancer stem cells; cell proliferation; cell signaling; transcription factor