title: Mouse low-grade gliomas contain cancer stem cells with unique molecular and functional properties.
abstract: The availability of adult malignant glioma stem cells (GSCs) has provided unprecedented opportunities to identify the mechanisms underlying treatment resistance. Unfortunately, there is a lack of comparable reagents for the study of pediatric low-grade glioma (LGG). Leveraging a neurofibromatosis 1 (Nf1) genetically engineered mouse LGG model, we report the isolation of CD133(+) multi-potent low-grade glioma stem cells (LG-GSCs), which generate glioma-like lesions histologically similar to the parent tumor following injection into immunocompetent hosts. In addition, we demonstrate that these LG-GSCs harbor selective resistance to currently employed conventional and biologically targeted anti-cancer agents, which reflect the acquisition of new targetable signaling pathway abnormalities. Using transcriptomic analysis to identify additional molecular properties, we discovered that mouse and human LG-GSCs harbor high levels of Abcg1 expression critical for protecting against ER-stress-induced mouse LG-GSC apoptosis. Collectively, these findings establish that LGG cancer stem cells have unique molecular and functional properties relevant to brain cancer treatment.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Lucy D'Agostino
authors.initials: LD
authors.lastname: McGowan
authors.affiliation: Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Cimino
authors.affiliation: Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sonika
authors.initials: S
authors.lastname: Dahiya
authors.affiliation: Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Leonard
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Da Yong
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: gutmannd@neuro.wustl.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
mesh_terms: D000071916:AC133 Antigen; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm; D059865:Endoplasmic Reticulum Stress; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: C487540:ABCG1 protein, mouse; D000071916:AC133 Antigen; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; D008074:Lipoproteins; D025542:Neurofibromin 1; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse