Chitinase-3-like protein 1 depletion in glioma cells alters tumor microenvironment and normalizes neovasculature in human glioma xenografts

Abstract Chitinase-3-like protein 1 (CHI3L1) is a secreted, non-enzymatic glycoprotein that interacts with cell-surface and extracellular-matrix proteins, proteoglycans, and polysaccharides. Many studies reported the overexpression of CHI3L1 in various cancers, but its exact role in tumorigenesis/cancer progression remains elusive. We performed a comprehensive analysis of CHI3L1 expression in public repositories including single-cell RNAseq datasets to determine the cellular source of CHI3L1 expression in gliomas. The highest CHI3L1 expression was detected in glioblastoma (GBM), a high-grade diffusive brain tumor with dismal survival prognosis. CHI3L1 knockout (KO) in human U87-MG glioma cells grossly affected transcriptional profiles and in vitro invasiveness of these cells, and strongly reduced the growth of intracranial U87-MG tumors in athymic mice. CHI3L1 KO in glioma cells resulted in normalization of tumor vasculature. Co-culture of CHI3L1 KO glioma cells with astrocytes upregulated aquaporin 4 (AQP4) in p38/MAPK and IL-1β/NFκB-dependent manner. Diminished infiltration of glioma-associated myeloid cells in CHI3L1 KO tumors was associated with reduction in SPP1 expression in CHI3L1 KO cells. Altogether, we demonstrate that CHI3L1 depletion affects several mechanisms crucial for GBM progression, therefore its targeting represents a novel strategy to treat GBM patients.