Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma [scRNA-seq]
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ABSTRACT: Chi3l1 (Chitinase 3-like 1) is a secreted protein highly expressed in glioblastoma. Here, we show that exposure of glioma stem cells (GSCs) to Chi3l1 reduces the CD133+/SOX2+ cells and increases the CD44+/Chi3l1+ cells. Single cell RNA-seq and RNA velocity following incubation of GSCs with Chi3l1 show significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq reveals that Chi3l1 increases accessibility of promoters containing MAZ transcription factor footprint. Inhibition of MAZ directly regulates genes with highest expression in cellular clusters exhibiting significant cell state transitions.
Project description:Chi3l1 (Chitinase 3-like 1) is a secreted protein highly expressed in glioblastoma. Here, we show that exposure of glioma stem cells (GSCs) to Chi3l1 reduces the CD133+/SOX2+ cells and increases the CD44+/Chi3l1+ cells. Single cell RNA-seq and RNA velocity following incubation of GSCs with Chi3l1 show significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq reveals that Chi3l1 increases accessibility of promoters containing MAZ transcription factor footprint. Inhibition of MAZ directly regulates genes with highest expression in cellular clusters exhibiting significant cell state transitions.
Project description:CHI3L1 (Chitinase 3-like1) is one of the highest expressed genes in glioblastoma and is associated with therapy resistance and low survival of patients. Here, we show that exposure of glioma stem cells (GSCs) to CHI3L1 induces marked phenotypic and transcriptomic change from CD133+/SOX2+ pro-neural to CD44+/CHI3L1+ mesenchymal phenotype. CHI3L1 induces chromatin remodeling in GSCs and regulates accessibility of ZNF281, CTCFL, SOX9, and the OCT4-SOX2-TCF3-NANOG transcription factor complex that drive the CHI3L1-mediated mesenchymal “switch” and maintain GSC identity.
Project description:CHI3L1 (Chitinase-3-like protein 1), also known as YKL-40, has been associated with inflammation and cancer. Transcription profiling analysis was performed in FTC-133 thyroid cancer cells transfected with control siRNA or siRNAs against CHI3L1.
Project description:Purpose: This study aimed to investigate the potential impacts of the CHI3L1 gene on the progression of papillary thyroid carcinoma (PTC) and to propose novel therapeutic approaches. Methods: CHI3L1 expression in PTC was analyzed using public datasets. Cell proliferation was assessed using the CCK-8 assay and colony formation assay. Tumor growth was evaluated using nude mouse xenograft models. Cell invasion was evaluated using the transwell assay, while cell migration was assessed with the wound healing assay. Transcriptomic analysis was conducted to examine the molecular mechanism, and real-time quantitative PCR was performed for gene expression validation. Results: The findings revealed that CHI3L1 expression was upregulated in various cancers, mainly in PTC. Both in vitro and in vivo assays demonstrated that cell proliferation was suppressed when CHI3L1 was knocked down. Transcriptome sequencing indicated that CHI3L1 knockdown was associated with migration-related pathways and TP53 signaling pathway. Transwell assays showed reduced cell invasion upon CHI3L1 suppression, while wound healing assays demonstrated decreased cell migration. Following CHI3L1 silencing, real-time quantitative PCR verified the overexpression of TP53-related genes. Survival analysis further indicated a correlation between elevated CHI3L1 expression and reduced survival rates. Conclusion: This study identified that CHI3L1 was an oncogene in human papillary thyroid cells and suggested that it may influence tumorigenesis through the TP53 signaling pathway. Thus, CHI3L1 could serve as a potential therapeutic target for PTC patients.
Project description:To better understand how Chi3l1 regulates the TFH response, we analyzed the transcriptome of CXCR5+PD1+CD4+Lin- TFH cells from msLNs of WT and Chi3l1-/- mice on D14 post H. pylori infection.
Project description:With the rise of immunotherapies as a treatment option for various cancers, there is a critical need to understand the mechanisms through which cancers evade the immune system. In a subset of poor outcome Triple Negative Breast Cancers, cytotoxic T cells are excluded from the tumor nest and restricted to the surrounding stroma, a phenomenon known as stromal restriction. Data from genetically engineered mouse models and human tumors identified that the secreted cytokine Chitinase-3 like 1 regulates the spatial positioning of T cells in several tumor types including breast, lung and colon. We further demonstrate that Chi3l1 regulates the spatial exclusion of T cells through the direct induction and deposition of neutrophil extracellular traps. Given the importance T cell infiltration in the immune elimination of nascent tumors, the future targeting of Chi3l1 should improve immunotherapy efficacy and outcomes in patients with tumors characterized by a T cell excluded microenvironment.
Project description:Intervertebral disc degeneration is the main cause of low back pain and the mechanism of which is far from fully revealed. Although multiple factors are related to the intervertebral disc degeneration, inflammation and matrix metabolism dysregulation are the two key factors that play an important role in degeneration. Here, we found that inflammation-related factor CHI3L1 is highly regulated in the nucleus pulposus during degeneration in both RNA and protein level. Immunohistochemical analysis show that the expression of CHI3L1 are NP tissue specific, and increased significantly in the degenerated nucleus pulposus cells. The mechanism of CHI3L1 is thus studied in this experiment.
Project description:We report the differential mRNA expressino of WT and Chi3l1 KO Th1 cells. We cultured WT and Chi3l1 KO naive CD4 T cells under Th1 skewing condition : plate-bound anti-CD3/28 antibody (2ug/mL), IL-12 0.2ng/mL, IL-2 50U/mL, anti-IL-4 neutralizing antibody 2ug/mL, for 3 days. We found different Th1 regulatory and tumoricidal-related gene expression in Chi3l1 KO T cells.