Putative cancer stem cells have been identified in glioblastomas and are associated with radio- and chemo-resistance. Further knowledge about these cells is thus highly warranted for the development of better glioblastoma therapies.Gene expression analyses of 11 high-grade glioma cultures identified 2 subsets, designated type A and type B cultures. The type A cultures displayed high expression of CXCR4, SOX2, EAAT1, and GFAP and low expression of CNP, PDGFRB, CXCL12, and extracellular matrix proteins. Clinical significance of the 2 types was indicated by the expression of type A– and type B–defining genes in different clinical glioblastoma samples. Classification of glioblastomas with type A– and type B–defining genes generated 2 groups of tumors composed predominantly of the classical, neural, and/or proneural subsets and the mesenchymal subset, respectively. Furthermore, tumors with EGFR mutations were enriched in the group of type A samples. Type A cultures possessed a higher capacity to form xenograft tumors and neurospheres and displayed low or no sensitivity to monotreatment with PDGF- and IGF-1–receptor inhibitors but were efficiently growth inhibited by combination treatment with low doses of these 2 inhibitors. Furthermore, siRNA-induced downregulation of SOX2 reduced sphere formation of type A cultures, decreased expression of type A–defining genes, and conferred sensitivity to monotreatment with PDGF- and IGF-1–receptor inhibitors.The present study thus describes a tumor- and neurosphere-forming SOX2-dependent subset of glioblastoma cultures characterized by a gene expression signature similar to that of the recently described classical, proneural, and/or neural subsets of glioblastoma. The findings that resistance to PDGF- and IGF-1–receptor inhibitors is related to SOX2 expression and can be overcome by combination treatment should be considered in ongoing efforts to develop novel stem cell–targeting therapies.

3q26 is frequently amplified in several cancer types with a common amplified region containing 20 genes. To identify cancer driver genes in this region, we interrogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifically, we found that TLOC1 (SEC62) was selectively required for the proliferation of cell lines with 3q26 amplification. Increased TLOC1 expression induced anchorage independent growth and a second 3q26 gene, SKIL (SNON), facilitated cell invasion in immortalized human mammary epithelial cells. Expression of both TLOC1 and SKIL induced subcutaneous tumor growth. Proteomic studies demonstrated that TLOC1 binds to DDX3X, which is essential for TLOC1-induced transformation and affected protein translation. SKIL induced invasion through up-regulation of SLUG (SNAI2) expression. Together, these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be co-amplified in other regions with somatic copy number gain.