SWIM tool application to expression data of glioblastoma stem-like cell lines, corresponding primary tumors and conventional glioma cell lines

Giulia Fiscon,Paola Paci,Federica Conte

doi:10.1186/s12859-018-2421-x

Giulia Fiscon, Paola Paci + Show 1 more

Open Access

https://doi.org/10.1186/s12859-018-2421-x

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Abstract

BackgroundIt is well-known that glioblastoma contains self-renewing, stem-like subpopulation with the ability to sustain tumor growth. These cells – called cancer stem-like cells – share certain phenotypic characteristics with untransformed stem cells and are resistant to many conventional cancer therapies, which might explain the limitations in curing human malignancies. Thus, the identification of genes controlling the differentiation of these stem-like cells is becoming a successful therapeutic strategy, owing to the promise of novel targets for treating malignancies.MethodsRecently, we developed SWIM, a software able to unveil a small pool of genes – called switch genes – critically associated with drastic changes in cell phenotype. Here, we applied SWIM to the expression profiling of glioblastoma stem-like cells and conventional glioma cell lines, in order to identify switch genes related to stem-like phenotype.ResultsSWIM identifies 171 switch genes that are all down-regulated in glioblastoma stem-like cells. This list encompasses genes like CAV1, COL5A1, COL6A3, FLNB, HMMR, ITGA3, ITGA5, MET, SDC1, THBS1, and VEGFC, involved in “ECM-receptor interaction“ and “focal adhesion” pathways. The inhibition of switch genes highly correlates with the activation of genes related to neural development and differentiation, such as the 4-core OLIG2, POU3F2, SALL2, SOX2, whose induction has been shown to be sufficient to reprogram differentiated glioblastoma into stem-like cells. Among switch genes, the transcription factor FOSL1 appears as the brightest star since: it is down-regulated in stem-like cells; it highly negatively correlates with the 4-core genes that are all up-regulated in stem-like cells; the promoter regions of the 4-core genes harbor a consensus binding motif for FOSL1.ConclusionsWe suggest that the inhibition of switch genes in stem-like cells could induce the deregulation of cell communication pathways, contributing to neoplastic progression and tumor invasiveness. Conversely, their activation could restore the physiological equilibrium between cell adhesion and migration, hampering the progression of cancer. Moreover, we posit FOSL1 as promising candidate to orchestrate the differentiation of cancer stem-like cells by repressing the 4-core genes’ expression, which severely halts cancer growth and might affect the therapeutic outcome. We suggest FOSL1 as novel putative therapeutic and prognostic biomarker, worthy of further investigation.

Highlights

It is well-known that glioblastoma contains self-renewing, stem-like subpopulation with the ability to sustain tumor growth
From this prospective study emerges that glioblastoma accounts for 15.1% of all primary brain tumors and 46.1% of primary malignant brain tumors; it is more common in older adults especially in males, and is less common in children; it has the highest incidence among all malignant tumors, with 11890 cases predicted in 2015 and 12120 in 2016
We applied SWItchMiner SWIM [23, 24] – a software that we recently developed to unveil a small pool of genes critically associated with drastic changes in cell phenotype – to the expression data obtained by Affymetrix HG-U133 Plus 2.0 microrarrays of glioblastoma stem-like (GS) cell lines, corresponding primary tumors, and conventional glioma cell lines [25], publicly available on the Gene Expression Omnibus (GEO) repository [26]

Summary

Introduction

It is well-known that glioblastoma contains self-renewing, stem-like subpopulation with the ability to sustain tumor growth. The unique professional research organization CBTRUS provided a comprehensive summary of the current descriptive epidemiology of primary brain and central nervous system tumors in the United States population for diagnosis years 2008-2012 [3] From this prospective study emerges that glioblastoma accounts for 15.1% of all primary brain tumors and 46.1% of primary malignant brain tumors; it is more common in older adults especially in males (is about 1.6 times higher in males as compared to females), and is less common in children; it has the highest incidence among all malignant tumors, with 11890 cases predicted in 2015 and 12120 in 2016. Despite aggressive and multimodality treatments [6, 7], GBM mortality rate remains still very high especially when compared to other cancers such as breast and lung cancer [3] This finding is dramatically confirmed by the clinical data of 161 unique GBM patients available from The Cancer Genome Atlas (TCGA) Data Portal [8, 9]. These data point out that the 5-years survival rate is estimated to be achieved only from the 20% of the patients (Fig. 1)

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