Single-cell RNA-seq reveals the invasive trajectory and molecular cascades underlying glioblastoma progression.

Bo Pang,Fenghua Guo,Jing Hu,Mingjiang Cheng,Jinyuan Xu,Lin Pang,Linyun Wan

doi:10.1002/1878-0261.12569

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor, in which GBM stem cells (GSCs) were identified to contribute to aggressive phenotypes and poor prognosis. Yet, how GSCs progress to invasive cells remains largely unexplored. Here, we revealed the cell subpopulations with distinct functional status and the existence of cells with high invasive potential within heterogeneous primary GBM tumors. We reconstructed a branched trajectory by pseudotemporal ordering of single tumor cells, in which the root showed GSC‐like phenotype while the end displayed high invasive activity. Thus, we further determined a path along which GSCs gradually transformed to invasive cells, called the ‘stem‐to‐invasion path’. Along this path, cells showed incremental expression of GBM invasion‐associated signatures and diminishing expression of GBM stem cell markers. These findings were validated in an independent single‐cell data set of GBM. Through analyzing the molecular cascades underlying the path, we identify crucial factors controlling the attainment of invasive potential of tumor cells, including transcription factors and long noncoding RNAs. Our work provides novel insights into GBM progression, especially the attainment of invasive potential in primary tumor cells, and supports the cancer stem cell model, with valuable implications for GBM therapy.

Highlights

Glioblastoma (GBM) is the most common and highly aggressive primary tumor of the central nervous system with extremely poor prognosis despite intensive treatment (Murray et al, 2014)
Invasion and metastasis were the late events during tumor development and progression, which is considered to be attributed to cancer stem cells (CSCs) by many studies (JaraizRodriguez et al, 2017; Liu et al, 2015; Miao et al, 2015)
Based on the above findings, we considered that the cells travelled from B1 through branch point 2, state 2, and to B3, representing the tumor progression from GBM stem cells (GSCs) to invasive cells, during which the CSC scores gradually decreased and invasive scores gradually increased as a function of pseudotime (Fig. 3E,F and Fig. S2C)

Summary

Introduction

Glioblastoma (GBM) is the most common and highly aggressive primary tumor of the central nervous system with extremely poor prognosis despite intensive treatment (Murray et al, 2014). Increasing evidence has shown that epithelial–mesenchymal transition (EMT) and dissemination can occur early during cancer progression (Eyles et al, 2010; Hosseini et al, 2016; Linde et al, 2018; Rhim et al, 2012). These studies suggest that cells may acquire the invasive and metastatic ability in primary tumors, which have been ready to disseminate to distant sites and contribute to the high heterogeneity of tumors especially GBM

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Conclusion