Abstract
Glioblastomas (GBM) exhibit intratumoral heterogeneity of various oncogenic evolutional processes. We have successfully isolated and established two distinct cancer cell lines with different morphological and biological characteristics that were derived from the same tissue sample of a GBM. When we compared their genomic and transcriptomic characteristics, each cell line harbored distinct mutation clusters while sharing core driver mutations. Transcriptomic analysis revealed that one cell line was undergoing a mesenchymal transition process, unlike the other cell line. Furthermore, we could identify four tumor samples containing our cell line-like clusters from the publicly available single-cell RNA-seq data, and in a set of paired longitudinal GBM samples, we could confirm three pairs where the recurrent sample was enriched in the genes specific to our cell line undergoing mesenchymal transition. The present study provides direct evidence and a valuable source for investigating the ongoing process of subcellular mesenchymal transition in GBM, which has prognostic and therapeutic implications.
Highlights
Glioblastoma (GBM) is the most common primary malignant brain tumor and is one of the most aggressive cancers [1]
These findings provide direct evidence to support the subcellular evolution of mesenchymal transition in GBM, which can be utilized in future investigations into intratumoral heterogeneity and the mesenchymal transition process
Chromosomal abnormalities of Epidermal growth factor receptor (EGFR) gene amplification and chromosome 9p21/p16 locus deletion were revealed by fluorescence in situ (S1f, S1g)
Summary
Glioblastoma (GBM) is the most common primary malignant brain tumor and is one of the most aggressive cancers [1]. Epithelial to mesenchymal transition, an EMT process, is a highly controversial term in GBM tumorigenesis. Another study reported the onco-plasticity of EMT-like or mesenchymal to epithelial transition (MET)-like conversion mediated by the epigenetic changes in the tumor microenvironment around glioma stem cells [4]. EMT has been widely described as a key factor that drives cellular heterogeneity influenced by both genetic and non-genetic determinants and even a small number of cells undergoing this process can cause evident intratumoral heterogeneity in cancers [8, 9]. The role of EMT and its clinical significance in GBM is still not well established due to the lack of direct evidence of its evolution in clinical samples and the rarity of cell lines that are derived from the same tissue to perform the verifying experiments
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