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

查看全文 作　　者：Xiaofei [1]Wang;Ran [2]Zhou;Yanzhen [1,3]Xiong;Lingling [1]Zhou;Xiang [1]Yan;Manli [4]Wang;Fan [1]Li;Chuanxing [1]Xie;Yiming [2]Zhang;Zongyao [1]Huang;Chaoqiong [1]Ding;Kaidou [4]Shi;Weida [5]Li;Yu [4]Liu;Zhongwei [2]Cao;Zhen-Ning [5]Zhang;Shengtao [2]Zhou;Chong [4]Chen;Yan [3]Zhang;Lu [2]Chen;Yuan [1]Wang 高影响力作者 机构地区：[1]Department of Neurology and Department of Neurosurgery,State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University and National Collaborative Innovation Center,Chengdu,Sichuan 610041,China;[2]Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE,State Key Laboratory of Biotherapy,West China Second Hospital,Sichuan University,Chengdu,Sichuan 610041,China;[3]National Clinical Research Center for Geriatrics,State Key Laboratory of Biotherapy,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China;[4]Department of Hematology,State Key Laboratory of Biotherapy,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China;[5]Institute of Regenerative Medicine,Shanghai East Hospital,Tongji University,Shanghai 200092,China高影响力机构 出　　处：《Cell Research》索引2021年第31卷第6期,共19页高影响力期刊 基　　金：supported by the National Key Research and Development Program of China,Stem Cell and Translational Research(2017YFA0106500);the Distinguished Young Scientists Program of Sichuan Province(2019JDJQ0029);the 135 Program for Excellent Scholars at West China Hospital(ZYYC20019);L.C.is supported by the National Key Research and Development Program of China,Stem Cell and Translational Research(2017YFA0106800 and 2017YFA0106500);the National Science Fund for Excellent Young Scholars(81722004);YZ.is supported by the National Key Research and Development Program of China,Stem Cell and Translational Research(2017YFA0106800). 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-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. 关 键 词：GLIOMA MALIGNANT alterations
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