Even with this therapeutic approach, tumor recurrence is inevitable ( 2) mainly due to the presence of glioma stem cells (GSC), which are characterized by high migratory potential ( 3), resistance to chemotherapy and radiation and the ability to form recurrent tumors ( 4). Standard treatment of glioblastoma includes surgical resection followed by radiation in the vicinity of the resection cavity and administration of temozolomide ( 1). Glioblastoma is the most prevalent and aggressive primary brain tumor. The role of Chi3l1 in regulating cellular plasticity confers a targetable vulnerability to glioblastoma. 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. Finally, targeting Chi3l1 in vivo with a blocking antibody inhibited tumor growth and increased the probability of survival. 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. ATAC-seq revealed that Chi3l1 increases accessibility of promoters containing a Myc-associated zinc finger protein (MAZ) transcription factor footprint. 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. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of β-catenin, Akt, and STAT3. Exposure of patient-derived GSCs to Chi3l1 reduced the frequency of CD133 +SOX2 + cells and increased the CD44 +Chi3l1 + cells. Here, we show that Chi3l1 alters the state of glioma stem cells (GSC) to support tumor growth. Chitinase 3–like 1 (Chi3l1) is a secreted protein that is highly expressed in glioblastoma.
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