Abstract
Glioblastoma (GBM) is the most common malignant adult brain tumor generally associated with high level of cellular heterogeneity and a dismal prognosis. Long noncoding RNAs (lncRNAs) are emerging as novel mediators of tumorigenesis. Recently developed single-cell RNA-seq provides an unprecedented way for analysis of the cell-to-cell variability in lncRNA expression profiles. Here we comprehensively examined the expression patterns of 2,003 lncRNAs in 380 cells from five primary GBMs and two glioblastoma stem-like cell (GSC) lines. Employing the self-organizing maps, we displayed the landscape of the lncRNA expression dynamics for individual cells. Further analyses revealed heterogeneous nature of lncRNA in abundance and splicing patterns. Moreover, lncRNA expression variation is also ubiquitously present in the established GSC lines composed of seemingly identical cells. Through comparative analysis of GSC and corresponding differentiated cell cultures, we defined a stemness signature by the set of 31 differentially expressed lncRNAs, which can disclose stemness gradients in five tumors. Additionally, based on known classifier lncRNAs for molecular subtypes, each tumor was found to comprise individual cells representing four subtypes. Our systematic characterization of lncRNA expression heterogeneity lays the foundation for future efforts to further understand the function of lncRNA, develop valuable biomarkers, and enhance knowledge of GBM biology.
Highlights
Glioblastoma (GBM), the most common and aggressive form of primary malignant brain tumor in adults, is one of the most lethal human cancers [1]
Identification of Long noncoding RNAs (lncRNAs) in single cells from GBM tumors and glioblastoma stem-like cell (GSC) lines We reanalyzed a previously reported transcriptome dataset that profiled 576 single cells isolated from five primary GBMs (MGH26, 28, 29, 30, 31), 96 resequenced MGH30 cells (MGH30L), 192 single cells from two GSC lines (GBM6 and GBM8) and 11 population samples [11]
GBM, as an archetypal example of a heterogeneous cancer, is well worthy of being considered for full assessment of expression changes in lncRNAs at the single-cell level. This is because compelling evidence shows many lncRNAs play an essential role in gliomagenesis [17, 21] and in addition, there exist copious single-cell RNA-seq transcriptome data [11]
Summary
Glioblastoma (GBM), the most common and aggressive form of primary malignant brain tumor in adults, is one of the most lethal human cancers [1]. GBM has manifested its heterogeneous nature in many ways It is, becoming increasingly clear that intratumoral genetic heterogeneity is central to GBM biology, potentially posing a great challenge to effective treatment [5]. Further supportive evidence comes from the observation that spatially distinct fragments sampled from the same tumor corresponded to different GBM molecular www.impactjournals.com/oncotarget subtypes [7]. These findings represent an important step toward understanding intratumoral heterogeneity, but they deserve closer scrutiny at higher resolution because each cell within a single tumor possibly possesses a unique gene expression signature under specific conditions
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