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

Abstract

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.

A clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1

“…STAT3 was predicted to be activated and to serve as a signaling hub in CHI3L1 OE PDGCLs (Supplementary Fig. 11d ), which matched previous studies 31 , 40 . Interestingly, STAT3 signaling was previously associated with elevated GAP43(pS41) levels 41 – pinpointing towards a potential link between the findings made in this study.…”

An automated archival single-nucleus total RNA sequencing platform mapping integrative and retrospective cell atlas of gliomas

“…3c ). CHI3L1 , a gene previously implicated in supporting tumor growth by influencing the state of glioma stem cells 20 , exhibited high expression in the MES-like subcluster. The lncRNA OBI1-AS1 , previously recognized as an astrocyte marker with a possible role in glioma recurrence and progression 21 , showed high expression in the AC-like 2 subcluster.…”

Chitin-mediated blockade of chitinase-like proteins reduces tumor immunosuppression, inhibits lymphatic metastasis and enhances anti-PD-1 efficacy in complementary TNBC models

“…The most investigated CLP family member in the context of cancer is CHI3L1, being of specific interest due to its conserved expression in both mice and humans [ 11 ]. The strategy of blocking CHI3L1 with specific antibodies has been used in mouse models to decrease progression of melanoma [ 38 – 40 ], glioblastoma [ 41 ], lung [ 35 , 42 ], pancreatic [ 35 ], colon [ 35 ] and breast cancer [ 16 ]. In marked contrast, the immunomodulatory effects envisaged after a more general blocking strategy of CLPs, especially in cancer and TNBC, have merely been investigated after chitin was twice opted for this purpose by the same group more than a decade ago [ 20 , 21 ].…”