Chi3l1（几丁质酶3样蛋白1）是一种分泌的蛋白质，在胶质母细胞瘤中高表达。在这里，我们展示了Chi3l1如何改变胶质瘤干细胞（GSCs）的状态以支持肿瘤生长。将来自患者的GSCs暴露在Chi3l1中会降低CD133 + SOX2 +细胞的频率，增加CD44 + Chi3l1 +细胞。Chi3l1结合到CD44并诱导β-catenin、Akt和STAT3的磷酸化和核转运。单细胞RNA-seq和RNA速度显示，将GSCs与Chi3l1孵育后，GSC状态动力学有重大变化，驱动GSCs向间充质表达丰富的分子表型转换，并降低向终端细胞状态转换的概率。ATAC-seq揭示Chi3l1增加了含有MAZ转录因子足迹的启动子的可及性。抑制MAZ会下调一组在接受Chi3l1处理后经历显着细胞状态转换的细胞簇中表达高的基因，而MAZ缺陷会拯救Chi3l1诱导的GSC自我更新的增加。最后，使用阻断抗体在体内针对Chi3l1可以抑制肿瘤生长并增加生存概率。总之，这项工作表明，Chi3l1与胶质瘤干细胞表面的CD44相互作用，诱导Akt/β-catenin信号和MAZ转录活性，进而在间充质型前馈回路中升高CD44表达。Chi3l1在调节细胞可塑性方面的作用赋予胶质母细胞瘤一种可靶向的易感性。

Chi3l1 (chitinase 3-like 1) is a secreted protein that is highly expressed in glioblastoma. Here, we show that Chi3l1 alters the state of glioma stem cells (GSCs) 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-seq 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 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 glioma stem cells 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.