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

• 作者: Xiaofei Wang Ran Zhou Yanzhen Xiong Lingling Zhou Xiang Yan Manli Wang Fan Li Chuanxing Xie Yiming Zhang Zongyao Huang Chaoqiong Ding Kaidou Shi Weida Li Yu Liu Zhongwei Cao Zhen-Ning Zhang Shengtao Zhou Chong Chen Yan Zhang Lu Chen Yuan Wang
• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2021,（6）
• 所属期刊栏目: ARTICLES
• 页码范围: 684-702
• 页数: 19页
• 语种: 英文

摘要

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-tike 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.