title: Sox2 promotes malignancy in glioblastoma by regulating plasticity and astrocytic differentiation.
abstract: The high-mobility group-box transcription factor sex-determining region Y-box 2 (Sox2) is essential for the maintenance of stem cells from early development to adult tissues. Sox2 can reprogram differentiated cells into pluripotent cells in concert with other factors and is overexpressed in various cancers. In glioblastoma (GBM), Sox2 is a marker of cancer stemlike cells (CSCs) in neurosphere cultures and is associated with the proneural molecular subtype. Here, we report that Sox2 expression pattern in GBM tumors and patient-derived mouse xenografts is not restricted to a small percentage of cells and is coexpressed with various lineage markers, suggesting that its expression extends beyond CSCs to encompass more differentiated neoplastic cells across molecular subtypes. Employing a CSC derived from a patient with GBM and isogenic differentiated cell model, we show that Sox2 knockdown in the differentiated state abolished dedifferentiation and acquisition of CSC phenotype. Furthermore, Sox2 deficiency specifically impaired the astrocytic component of a biphasic gliosarcoma xenograft model while allowing the formation of tumors with sarcomatous phenotype. The expression of genes associated with stem cells and malignancy were commonly downregulated in both CSCs and serum-differentiated cells on Sox2 knockdown. Genes previously shown to be associated with pluripontency and CSCs were only affected in the CSC state, whereas embryonic stem cell self-renewal genes and cytokine signaling were downregulated, and the Wnt pathway activated in differentiated Sox2-deficient cells. Our results indicate that Sox2 regulates the expression of key genes and pathways involved in GBM malignancy, in both cancer stemlike and differentiated cells, and maintains plasticity for bidirectional conversion between the two states, with significant clinical implications.
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI.
authors.forename: Artem D
authors.initials: AD
authors.lastname: Berezovsky
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI.
authors.forename: Laila M
authors.initials: LM
authors.lastname: Poisson
authors.affiliation: Program of Translational Medicine, Van Andel Research Institute, Grand Rapids, MI.
authors.forename: David
authors.initials: D
authors.lastname: Cherba
authors.affiliation: Program of Translational Medicine, Van Andel Research Institute, Grand Rapids, MI.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Webb
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Transou
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI.
authors.forename: Nancy W
authors.initials: NW
authors.lastname: Lemke
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI.
authors.forename: Xin
authors.initials: X
authors.lastname: Hong
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Hasselbach
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Irtenkauf
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI; Department of Neurology, Henry Ford Hospital, Detroit, MI.
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.affiliation: Department of Neurosurgery, Henry Ford Hospital, Detroit, MI. Electronic address: adecarv1@hfhs.org.
authors.forename: Ana C
authors.initials: AC
authors.lastname: deCarvalho
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D009473:Neuronal Plasticity / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors
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