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Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184698 | GEO | 2022/10/24

REPOSITORIES: GEO

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

Project description: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.SignificanceChi3l1 is a modulator of glioma stem cell states that can be targeted to promote differentiation and suppress growth of glioblastoma.

| S-EPMC10267676 | biostudies-literature

Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma [scRNA-seq]

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.

2022-10-24 | GSE184696 | GEO

Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma [RNA-seq]

2022-10-24 | GSE184695 | GEO

Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma

Project description:Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma

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Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma [RNA-seq]

Project description:Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma [RNA-seq]

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Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma [scRNA-seq]

Project description:Chi3l1 is a modulator of glioma stem cell states and a therapeutic vulnerability for glioblastoma [scRNA-seq]

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A Transcriptional State Driven by Yin Yang 1 Confers a Therapeutic Vulnerability in Glioblastoma Stem Cells

Project description:This SuperSeries is composed of the SubSeries listed below.

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Chromatin states and Transcriptome in in glioblastoma stem cells

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The MDM2-p53 Axis Represents a Therapeutic Vulnerability Unique to Glioma Stem Cells.

Project description:The prevention of tumor recurrence by the successful targeting of glioma stem cells endowed with a tumor-initiating capacity is deemed the key to the long-term survival of glioblastoma patients. Glioma stem cells are characterized by their marked therapeutic resistance; however, recent evidence suggests that they have unique vulnerabilities that may be therapeutically targeted. We investigated MDM2 expression levels in glioma stem cells and their non-stem cell counterparts and the effects of the genetic and pharmacological inhibition of MDM2 on the viability of these cells as well as downstream molecular pathways. The results obtained showed that MDM2 expression was substantially higher in glioma stem cells than in their non-stem cell counterparts and also that the inhibition of MDM2, either genetically or pharmacologically, induced a more pronounced activation of the p53 pathway and apoptotic cell death in the former than in the latter. Specifically, the inhibition of MDM2 caused a p53-dependent increase in the expression of BAX and PUMA and a decrease in the expression of survivin, both of which significantly contributed to the apoptotic death of glioma stem cells. The present study identified the MDM2-p53 axis as a novel therapeutic vulnerability, or an Achilles' heel, which is unique to glioma stem cells. Our results, which suggest that non-stem, bulk tumor cells are less sensitive to MDM2 inhibitors, may help guide the selection of glioblastoma patients suitable for MDM2 inhibitor therapy.

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Aberrant differentiation of glioma stem cells: Implications for therapeutic targeting

Project description:This SuperSeries is composed of the SubSeries listed below.

2015-09-01 | GSE58924 | GEO