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.

MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma

“…S6). These findings are consistent with our RNA-seq analysis and with previous published results showing that SOX2 is widely expressed in primary glioma, but is reduced in recurrent glioma (22).…”

“…These findings suggest that the NE regions of proneural gliomas predominantly contain OLIG2 + , OPC-like glioma cells, whereas NE regions of mesenchymal gliomas contain a larger proportion of CD44 + astrocyte-like tumor cells. Notably, Sox2, a proneural classifier gene and stem cell marker that has been implicated in glioma growth and progression (21,22) is expressed by both OLIG2 + cells and CD44 + cells. Immunohistochemical stains of NE glioma samples showed that SOX2 is expressed in a high percentage of infiltrating glioma cells in primary samples; however, recurrent gliomas showed a significantly lower SOX2 labeling index (SI Appendix, Fig.…”

ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis

“…7 Translocations involving NCOA2 have been observed in mesenchymal chondrosarcoma, spindle cell rhabdomyosarcoma, prostate cancer, colon cancer, acute leukemia, and soft tissue angiofibroma, whereas ETV3 abnormalities have been For [6][7][8][9] Neoplastic associations of ICH are limited to case reports that include patients with mast cell leukemia, acute myeloid leukemia, and B-cell lymphoma.…”

Differential expression of CXCR4 and CXCR7 with various stem cell markers in paired human primary and recurrent glioblastomas

“…An embryonic stem cell gene signature is well known to correlate with a more undifferentiated phenotype in various cancers (28), and a large scale tissue microarray analysis including 80 low-grade and 98 high-grade gliomas showed an upregulated protein level of NANOG, KLF-4, OCT-4 and SOX-2 in highgrade gliomas (29). Several other studies also point to the relevance of neural and embryonic stem cell markers in GBM progression (30)(31)(32)(33)(34)(35)(36). In the present study we showed that both neural and embryonic stem cells markers are preferentially co-expressed with CXCR4 in matched samples of primary and recurrent GBM pairs, whereas CXCR7 was mostly found on stem cell marker negative cells.…”