American Association for Cancer Research
Browse
can-21-3629_supplementary_table_1_suppst1.pdf (76.44 kB)

Supplementary Table 1 from Chi3l1 Is a Modulator of Glioma Stem Cell States and a Therapeutic Target in Glioblastoma

Download (76.44 kB)
journal contribution
posted on 2023-06-15, 08:20 authored by Charlotte Guetta-Terrier, David Karambizi, Bedia Akosman, John P. Zepecki, Jia-Shu Chen, Suchitra Kamle, J. Eduardo Fajardo, Andras Fiser, Ritambhara Singh, Steven A. Toms, Chun Geun Lee, Jack A. Elias, Nikos Tapinos

Supplementary Table 1

Funding

Warren Alpert Foundation (WAF)

History

ARTICLE ABSTRACT

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. Chi3l1 is a modulator of glioma stem cell states that can be targeted to promote differentiation and suppress growth of glioblastoma.

Usage metrics

    Cancer Research

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC