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Glioblastoma (GBM) is one of the most aggressive human tumors. Recent studies have shown that GBM “aggressiveness” is mainly due to populations of glioma stem cells (GSCs) within the tumor mass, which exhibit high migratory potential [3–5], form secondary tumors and can resist chemotherapy and radiation [6]. GSCs exhibit remarkable plasticity, are able to transition between immature and differentiated stages as well as reversibly express various phenotypic markers depending on the tumor microenvironment [7, 8]. Given such challenging features, GSCs have been subject of extensive research. YKL-40 (or Chitinase 3-like1) is a secreted glycoprotein normally expressed by numerous cell types including neutrophils and macrophages [11]. YKL-40 is highly expressed in numerous types of cancer such as breast, colon, lung, ovary, prostate, rectum and GBM [12–15]. RNA-seq on patient-derived GBMs and TCGA database analysis, showed that YKL-40 is one of the highest expressed genes in GBM. YKL-40 expression is associated with the invasiveness, therapy resistance and low survival rate of patients [16]. Here, we aim to elucidate the mechanistic function of YKL-40 in the microenvironment of human glioblastomas and determine its role as a new therapeutic target. We hypothesize that YKL-40 regulates transitions of GSCs phenotypes that underlie glioblastoma invasiveness and aggression. Our preliminary data show that incubation of patient-derived GSCs with YKL-40 induces a marked phenotypic change of GSCs from CD133+/Sox2+ to CD44+/YKL40+. We also performed RNA-seq and ATAC-seq to study the role of YKL-40 in gene expression and chromatin accessibility and identified the YKL-40-modulated transcriptional regulatory network that drives the phenotypic “switch” of GSCs. Finally, we used a novel humanized monoclonal antibody against YKL-40 to treat orthotopic glioblastoma xenografts and show significant reduction of tumor volume. Our work implicates YKL-40 as a microenvironment modulator of GSC phenotypic transitions and demonstrates pre-clinical efficacy of targeting YKL-40 to reduce tumor burden.

TMIC-40. YKL-40 AS MODULATOR OF CANCER STEM CELL PHENOTYPIC TRANSITIONS IN HUMAN GLIOBLASTOMAS