Unraveling unique and common cell type-specific mechanisms in glioblastoma multiforme

Abstract

Glioblastoma multiforme persists to be an enigmatic distress in neuro-oncology. Its untethering capacity to thrive in a confined microenvironment, metastasize intracranially, and remain resistant to the systemic treatments, renders this tumour incurable. The glial cell type specificity in GBM remains exploratory. In our study, we aimed to address this problem by studying the GBM at the cell type level in the brain. The cellular makeup of this tumour is composed of genetically altered glial cells which include astrocyte, microglia, oligodendrocyte precursor cell, newly formed oligodendrocyte and myelinating oligodendrocyte. We extracted cell type-specific solid tumour as well as recurrent solid tumour glioma genes, and studied their functional networks and contribution towards gliomagenesis. We identified the principal transcription factors that are found to be regulating vital tumorigenic processes. We also assessed the protein-protein interaction networks at their domain level to get a more microscopic view of the structural and functional operations that transpire in these cells. This yielded the eminent protein regulators exhibiting their regulation in signaling pathways. Overall, our study unveiled regulatory mechanisms in glioma cell types that can be targeted for a more efficient glioma therapy.

Keywords: CAMs, Cell adhesion molecules; CNS, Cental nervous system; DEG, Differentially expressed genes; EMT, Epithelial-mesenchymal transistion; GBM, Glioblastoma multiforme; GSC, Glioblastoma Stem Cell; Glial cell types; Glioblastoma multiforme; INstruct, a database of structurally resolved protein interactome; MO, Myelinating oligodendrocyte; NCBI, National Centre for Biotechnology Information; NFO, Newly formed oligodendrocyte; NPC, Neural progenitor cell; OPC, Oligodendrocyte precursor cell; PDI, Protein domain interactions; PDIN, Protein domain interaction network; PPI, Protein-protein interactions; Primary solid tumour; Protein domains; Protein interaction networks; RSEM, RNA-seq by Expectation-Maximization; Recurrent solid tumour transcription factors; SIGNOR, Signaling Network Open Resource; TCGA, The Cancer Genome Atlas; TF, Transcription factor; TP, Primary solid tumour; TR, Recurrent solid tumour; WHO, World health organization; iDEP, Integrated Differential Expression and Pathway analysis.

Graphical abstract

Fig. 1

RNA-sequencing analysis of GBM. (A) Schematic representation of acquiring cell type-specific GBM data and the consolidative analyses. (B-C) GBM hierarchical clustering analysis of normal brain, TP and normal brain, TR cancer patients, respectively. (D-E) Differential gene expression analysis of GBM TP and TR.

Fig. 2

Unique and common glial cell type-specific glioma genes. (A-B) The UpSet plot displaying the glioma-specific unique and common genes across cell types in TP and TR.

Fig. 3

Top TP DEGs unique and common across cell types. The volcano plots exhibiting top upregulated and downregulated genes between TP glioma and cell types.

Fig. 4

Top TR DEGs unique and common across cell types. The volcano plots exhibiting top upregulated and downregulated genes between TR glioma and cell types.

Fig. 5

Unique and common TFs in glioma cell types. (A-B) The UpSet plots represent TP and TR transcription factors (TFs) unique and common in astrocyte, microglia, OPC, NFO and MO.

Fig. 6

Transcription factor network analysis in TP GBM cell types. (A-H) TF-TF correlation networks displaying hierarchical transcriptional influence of TFs. Note: Red and blue indicate up and down regulation, respectively.

Fig. 7

Pathway enrichment analysis of transcription factors. (A-H) The heatmaps depict the most significant (P ≤ 0.05) pathways in and across TP astrocyte, microglia, OPC, NFO and MO regulated by the TFs.

Fig. 8

Protein-domain interaction network (PDIN) analysis of TP proteins in cell types. (A-O) Comprehensive visualization of PDINs in each cell type and the most significant (Padj ≤ 0.05) pathways they participate in. The bar plots illustrate the top protein regulators and the number of proteins they regulate in astrocyte, microglia, OPC, NFO and MO.

Fig. 9

Protein-domain interaction network (PDIN) analysis of TR proteins in cell types. (A-B) Comprehensive visualization of PDINs in each cell type and the most significant (Padj ≤ 0.05) pathways they participate in.

Fig. 10

Protein domain interactions (PDIs) between cell types. (A-B) PDIs in and across cell types with their functions in TP and TR, respectively.

Fig.11

Graphical abstract of our findings. Depiction of prospective gliomagenesis model in GBM at its cell type level.