Chi3l1 Is a Modulator of Glioma Stem Cell States and a Therapeutic Target in Glioblastoma

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 thorn SOX2 thorn cells and increased the CD44 thorn Chi3l1 thorn cells. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of (3-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 foot-print. 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/(3-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.

Automated summary

Chi3l1 is a secreted protein highly expressed in glioblastoma that alters the state of glioma stem cells (GSC) and supports tumor growth. It interacts with CD44, inducing Akt/(3-catenin signaling and MAZ transcriptional activity, leading to a pro-mesenchymal feed-forward loop and increased GSC self-renewal. Targeting Chi3l1 with a blocking antibody inhibits tumor growth and improves survival, making it a potential therapeutic target for glioblastoma.