title: Regulation of Glioblastoma Tumor-Propagating Cells by the Integrin Partner Tetraspanin CD151.
abstract: Glioblastoma (GBM) stem cells (GSCs) represent tumor-propagating cells with stem-like characteristics (stemness) that contribute disproportionately to GBM drug resistance and tumor recurrence. Understanding the mechanisms supporting GSC stemness is important for developing therapeutic strategies for targeting GSC-dependent oncogenic mechanisms. Using GBM-derived neurospheres, we identified the cell surface tetraspanin family member CD151 as a novel regulator of glioma cell stemness, GSC self-renewal capacity, migration, and tumor growth. CD151 was found to be overexpressed in GBM tumors and GBM neurospheres enriched in GSCs. Silencing CD151 inhibited neurosphere forming capacity, neurosphere cell proliferation, and migration and attenuated the expression of markers and transcriptional drivers of the GSC phenotype. Conversely, forced CD151 expression promoted neurosphere self-renewal, cell migration, and expression of stemness-associated transcription factors. CD151 was found to complex with integrins α3, α6, and β1 in neurosphere cells, and blocking CD151 interactions with integrins α3 and α6 inhibited AKT phosphorylation, a downstream effector of integrin signaling, and impaired sphere formation and neurosphere cell migration. Additionally, targeting CD151 in vivo inhibited the growth of GBM neurosphere-derived xenografts. These findings identify CD151 and its interactions with integrins α3 and α6 as potential therapeutic targets for inhibiting stemness-driving mechanisms and stem cell populations in GBM.
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Tilghman
authors.affiliation: Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Schiapparelli
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Bachuchu
authors.initials: B
authors.lastname: Lal
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Ying
authors.affiliation: Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA; Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Quinones-Hinojosa
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Shuli
authors.initials: S
authors.lastname: Xia
authors.affiliation: Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, 21205, USA; Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. Electronic address: laterra@kennedykrieger.org.
authors.forename: John
authors.initials: J
authors.lastname: Laterra
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D039422:Integrin alpha3 / Q000235:genetics*; D039503:Integrin alpha6 / Q000235:genetics*; D014411:Neoplastic Stem Cells; D060185:Tetraspanin 24 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C554715:CD151 protein, human; C000599264:ITGA3 protein, human; C588002:ITGA6 protein, human; D039422:Integrin alpha3; D039503:Integrin alpha6; D060185:Tetraspanin 24