title: ABCG2 regulates self-renewal and stem cell marker expression but not tumorigenicity or radiation resistance of glioma cells.
abstract: Glioma cells with stem cell traits are thought to be responsible for tumor maintenance and therapeutic failure. Such cells can be enriched based on their inherent drug efflux capability mediated by the ABC transporter ABCG2 using the side population assay, and their characteristics include increased self-renewal, high stem cell marker expression and high tumorigenic capacity in vivo. Here, we show that ABCG2 can actively drive expression of stem cell markers and self-renewal in glioma cells. Stem cell markers and self-renewal was enriched in cells with high ABCG2 activity, and could be specifically inhibited by pharmacological and genetic ABCG2 inhibition. Importantly, despite regulating these key characteristics of stem-like tumor cells, ABCG2 activity did not affect radiation resistance or tumorigenicity in vivo. ABCG2 effects were Notch-independent and mediated by diverse mechanisms including the transcription factor Mef. Our data demonstrate that characteristics of tumor stem cells are separable, and highlight ABCG2 as a potential driver of glioma stemness.
authors.affiliation: Cancer Biology and Genetics Program, New York, NY 10021, USA.|Brain Tumor Center, New York, NY 10021, USA.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Wee
authors.affiliation: Human Biology Division, Solid Tumor and Translational Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.|Neurosurgery and Alvord Brain Tumor Center, University of Washington, Seattle, WA 98104, USA.|Translational Cancer Research, Department of Laboratory Medicine, Lund University, SE-22363 Lund, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pietras
authors.affiliation: Human Biology Division, Solid Tumor and Translational Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.|Neurosurgery and Alvord Brain Tumor Center, University of Washington, Seattle, WA 98104, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Centro San Giovanni di Dio - Fatebenefratelli, IRCCS, 25123 Bs, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bazzoli
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Podlaha
authors.affiliation: HTS Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Antczak
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg-Nilsson
authors.affiliation: HTS Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Hakim
authors.initials: H
authors.lastname: Djaballah
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Department of Biostatistics, Harvard School of Public Health, Boston, MA 02215, USA.
authors.forename: Franziska
authors.initials: F
authors.lastname: Michor
authors.affiliation: Human Biology Division, Solid Tumor and Translational Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.|Neurosurgery and Alvord Brain Tumor Center, University of Washington, Seattle, WA 98104, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism*; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000528:radiation effects; D011836:Radiation Tolerance; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects; D015854:Up-Regulation
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D051880:Receptors, Notch