CD44细胞
癌症研究
生物
蛋白激酶B
干细胞
胶质瘤
SOX2
神经干细胞
癌症干细胞
细胞生物学
车站3
转录因子
信号转导
细胞
基因
遗传学
作者
Charlotte Guetta-Terrier,David Karambizi,Bedia Akosman,John P. Zepecki,Jia-Shu Chen,Suchitra Kamle,J. Eduardo Fajardo,András Fiser,Ritambhara Singh,Steven Toms,Chang-Min Lee,Jack A. Elias,Nikos Tapinos
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2023-04-27
卷期号:83 (12): 1984-1999
被引量:11
标识
DOI:10.1158/0008-5472.can-21-3629
摘要
Abstract Chitinase 3–like 1 (Chi3l1) is a secreted protein that is highly expressed in glioblastoma. Here, we show that Chi3l1 alters the state of glioma stem cells (GSC) to support tumor growth. Exposure of patient-derived GSCs to Chi3l1 reduced the frequency of CD133+SOX2+ cells and increased the CD44+Chi3l1+ cells. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of β-catenin, Akt, and STAT3. Single-cell RNA sequencing and RNA velocity following incubation of GSCs with Chi3l1 showed significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq revealed that Chi3l1 increases accessibility of promoters containing a Myc-associated zinc finger protein (MAZ) transcription factor footprint. Inhibition of MAZ downregulated a set of genes with high expression in cellular clusters that exhibit significant cell state transitions after treatment with Chi3l1, and MAZ deficiency rescued the Chi3L-induced increase of GSC self-renewal. Finally, targeting Chi3l1 in vivo with a blocking antibody inhibited tumor growth and increased the probability of survival. Overall, this work suggests that Chi3l1 interacts with CD44 on the surface of GSCs to induce Akt/β-catenin signaling and MAZ transcriptional activity, which in turn upregulates CD44 expression in a pro-mesenchymal feed-forward loop. The role of Chi3l1 in regulating cellular plasticity confers a targetable vulnerability to glioblastoma. Significance: Chi3l1 is a modulator of glioma stem cell states that can be targeted to promote differentiation and suppress growth of glioblastoma.
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