Volume 31, No 6, Jun 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 6, June 2021: 684-702   |  Open Access

ORIGINAL ARTICLES

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

Xiaofei Wang¹ , Ran Zhou² , Yanzhen Xiong^1,3 , Lingling Zhou¹ , Xiang Yan¹ , Manli Wang⁴ , Fan Li¹ , Chuanxing Xie¹ , Yiming Zhang² , Zongyao Huang¹ , Chaoqiong Ding¹ , Kaidou Shi⁴ , Weida Li⁵ , Yu Liu⁴ , Zhongwei Cao² , Zhen-Ning Zhang⁵ , Shengtao Zhou² , Chong Chen⁴ , Yan Zhang^3,* , Lu Chen^2,* , Yuan Wang^1,*

¹Department 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
²Key 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
³National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
⁴Department of Hematology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
⁵Institute of Regenerative Medicine, Shanghai East Hospital, Tongji University, Shanghai 200092, China
These authors contributed equally: Xiaofei Wang, Ran Zhou Correspondence: Yan Zhang(yanzhang@scu.edu.cn)Lu Chen(luchen@scu.edu.cn)Yuan Wang(wangyuan@scu.edu.cn)

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.

https://doi.org/10.1038/s41422-020-00451-z

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