Sequential fate-switches in stem-like cells drive the tumorigenic trajectory from human neural stem cells to malignant glioma

Abstract

Glioblastoma (GBM) is an incurable and highly heterogeneous brain tumor, originating from human neural stem/progenitor cells (hNSCs/hNPCs) years ahead of diagnosis. Despite extensive efforts to characterize hNSCs and end-stage GBM at bulk and single-cell levels, the de novo gliomagenic path from hNSCs is largely unknown due to technical difficulties in early-stage sampling and preclinical modeling. Here, we established two highly penetrant hNSC-derived malignant glioma models, which resemble the histopathology and transcriptional heterogeneity of human GBM. Integrating time-series analyses of whole-exome sequencing, bulk and single-cell RNA-seq, we reconstructed gliomagenic trajectories, and identified a persistent NSC-like population at all stages of tumorigenesis. Through trajectory analyses and lineage tracing, we showed that tumor progression is primarily driven by multi-step transcriptional reprogramming and fate-switches in the NSC-like cells, which sequentially generate malignant heterogeneity and induce tumor phenotype transitions. We further uncovered stage-specific oncogenic cascades, and among the candidate genes we functionally validated C1QL1 as a new glioma-promoting factor. Importantly, the neurogenic-to-gliogenic switch in NSC-like cells marks an early stage characterized by a burst of oncogenic alterations, during which transient AP-1 inhibition is sufficient to inhibit gliomagenesis. Together, our results reveal previously undercharacterized molecular dynamics and fate choices driving de novo gliomagenesis from hNSCs, and provide a blueprint for potential early-stage treatment/diagnosis for GBM.

A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma

“…Stemness phenotype in GBM is characterized by expressions of CD133 and the neural stem cell marker Nestin [ 7 , 8 , 9 , 10 , 11 ]. From a transcriptomics perspective, GSCs exploit normal neural stem cell developmental transcription mechanisms towards tumorigenesis adaptation [ 12 , 13 , 14 ]. Given the central role of stemness reprogramming in GBM resistance, it is therefore of utmost importance to identify and target essential stemness reprogramming mechanisms in GBM.…”

The mmu_circRNA_37492/hsa_circ_0012138 function as potential ceRNA to attenuate obstructive renal fibrosis

“…Accordingly, the expression of homologous gene and its predicted binding miRNA were assayed by western blot and RT-qPCR. Moreover, to further clarify the potential biological process and understand the potential pathways of differential expression mRNAs regulated by hsa_circ_0012138, we performed Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis using the R package ‘clusterProfiler’, and then visualized the top 10 terms [ 49 , 50 ].…”

Short-read and long-read full-length transcriptome of mouse neural stem cells across neurodevelopmental stages

“…The cells were then partitioned into Gel Beads in Emulsion in the Chromium instrument, where cell lysis and barcoded reverse transcription of RNA occurred, followed by amplification, shearing 5′ adapter, and sample index attachment. Libraries were sequenced on the Illumina NovaSeq 6000 platform at Novogene, Beijing, China 12 .…”

“…We used MuSiC to deconvolute the transcriptome of Bulk RNA-Seq samples into the likely constituent cell types, using scRNA-seq datasets from same samples as Bulk RNA-Seq as a reference. We calculated the predicted proportions of each cell type in bulk samples, and visualized these proportions with bar plot 12 .…”