Abstract
Glioblastoma, the most malignant brain cancer, contains self-renewing, stem-like cells that sustain tumor growth and therapeutic resistance. Identifying genes promoting stem-like cell differentiation might unveil targets for novel treatments. To detect them, here we apply SWIM – a software able to unveil genes (named switch genes) involved in drastic changes of cell phenotype – to public datasets of gene expression profiles from human glioblastoma cells. By analyzing matched pairs of stem-like and differentiated glioblastoma cells, SWIM identified 336 switch genes, potentially involved in the transition from stem-like to differentiated state. A subset of them was significantly related to focal adhesion and extracellular matrix and strongly down-regulated in stem-like cells, suggesting that they may promote differentiation and restrain tumor growth. Their expression in differentiated cells strongly correlated with the down-regulation of transcription factors like OLIG2, POU3F2, SALL2, SOX2, capable of reprogramming differentiated glioblastoma cells into stem-like cells. These findings were corroborated by the analysis of expression profiles from glioblastoma stem-like cell lines, the corresponding primary tumors, and conventional glioma cell lines. Switch genes represent a distinguishing feature of stem-like cells and we are persuaded that they may reveal novel potential therapeutic targets worthy of further investigation.
Highlights
Glioblastoma, the most malignant brain cancer, contains self-renewing, stem-like cells that sustain tumor growth and therapeutic resistance
The switch genes that we have identified in this work could have the potential to improve our knowledge of the cellular functions that are crucial for glioblastoma, such as the control of cancer stem-like cells differentiation and invasion
The dataset contains the global expression profiles obtained by RNA sequencing of matched pairs of cells derived from three different human tumors and grown either as stem-like tumour propagating cells or as differentiated glioblastoma cells
Summary
Glioblastoma, the most malignant brain cancer, contains self-renewing, stem-like cells that sustain tumor growth and therapeutic resistance. A subset of them was significantly related to focal adhesion and extracellular matrix and strongly down-regulated in stem-like cells, suggesting that they may promote differentiation and restrain tumor growth Their expression in differentiated cells strongly correlated with the down-regulation of transcription factors like OLIG2, POU3F2, SALL2, SOX2, capable of reprogramming differentiated glioblastoma cells into stem-like cells. Several studies identified a subpopulation of GBM cells with radio/chemotherapy-resistant properties that have a role in driving tumor initiation, progression, resistance to treatment, and relapse[11,12,13,14,15,16,17,18] Due to their abilities of self-renewal, proliferation, and differentiation into multiple lineages, these cells are named glioblastoma stem-like cells (GSCs) or tumor-propagating cells (TPCs)[19], and are held responsible for carcinogenesis. SWIM gave promising results in the study of the grapevine developmental shift from the immature to the mature growth phase[35], as well as in a multi-cancer analysis[34]
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