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CHI3L1 promotes proliferation and metastasis of ovarian cancer cells

ABSTRACT: Adipocyte-tumor interaction plays a critical role in tumor microenvironment. Typically, high-grade serous ovarian carcinoma (HGSOC) preferentially metastasizes to the omentum, an adipocyte-rich tissue, and obesity correlates with worse patient prognosis. However, the underlying mechanisms remain poorly understood. Here, we identify a bidirectional adipocyte–cancer cell axis in which HGSOC cells stimulate lactate metabolism in adjacent adipocytes, leading to hypoxia-inducible factor 1α (HIF-1α) activation and subsequent secretion of chitinase 3-like 1 (CHI3L1). On the one hand, CHI3L1 acts as an inflammatory factor that promotes the secretion of additional cytokines, perpetuating omental inflammation, driving CD8⁺ T cell exhaustion, and shaping an immunosuppressive microenvironment that favors tumor metastasis. On the other hand, CHI3L1 binds to and stabilizes protein arginine methyltransferase 5 (PRMT5) in tumor cells, thereby enhancing its methyltransferase activity. This upregulation suppresses dual-specificity phosphatase 1 (DUSP1), a phosphatase of mitogen-activated protein kinase (MAPK), and sustains oncogenic MAPK signaling across multiple tumor models. Obesity amplifies this pathway by heightening HIF-1α activity and elevating CHI3L1 levels in adipose tissue, which drives both tumor progression and resistance to anti-angiogenic therapy. Pharmacological inhibition of CHI3L1 disrupts this signaling loop and restores therapeutic sensitivity, while also alleviating immune exhaustion in the tumor microenvironment. Collectively, our findings establish CHI3L1 as a key mediator of a unified mechanism that drives omental tropism and obesity-associated aggressive phenotypes, highlighting its potential as a prognostic biomarker and therapeutic target to improve anti-angiogenic therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE341155 | GEO | 2026/07/27

REPOSITORIES: GEO

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Project description:Introduction. At present, the precise role of Spry proteins in tumor progression is still debated. Our previous study showed that Spry1 knockdown (Spry1KO) in BRAFV600-mutant cutaneous melanoma (CM) promoted cell cycle arrest and apoptosis, repressed cell proliferation in vitro, and reduced tumor growth in vivo. Furthermore, we observed that Spry1 loss impaired angiogenesis in vivo. Hypoxia has been recognized as one of the crucial features of CM. Hypoxia results in the activation of the transcription factor hypoxia-inducible factor 1α (HIF‐1α), which represents a master regulator of angiogenesis. Hence, the present study was designed to explore a possible role of Spry1 in modulating angiogenesis and hypoxia in CM. Materials and methods. SPRY1 gene was knocked-out using the CRISPR strategy in the BRAF wild-type (wt) Mel 313 and in the BRAF-mutant Mel 593 cell lines. Angiogenic potential was assessed through in vivo CD31 staining and in vitro tube formation assays. By using in vitro and in vivo models, the effects of Spry1KO on hypoxia-related genes were investigated through RNA-sequencing (RNA-seq), quantitative real-time PCR, western blot, and immunofluorescence analyses. To gain insight into Spry1 interactome, immunoprecipitation coupled to mass spectrometry (IP-MS) was employed. Results and discussion. Consistent with our previous data, tumors arising from Mel 313 and Mel 593 Spry1KO clones were significantly smaller than those from their corresponding parental cells. Tumor growth inhibition was accompanied by a substantial reduction of angiogenesis, as assessed by the immunofluorescence staining of CD31 in vivo and the tube formation assay in vitro. Accordingly, RNA-seq analysis indicated that the vascular endothelial growth factor A was significantly down-regulated following Spry1 silencing. Notably, Ingenuity Pathway Analysis identified “HIF-1α Signaling” as the most significant molecular and cellular function affected in vivo by Spry1 silencing regardless of the BRAF mutational status. Analyses of tumor tissues confirmed that Spry1KO significantly reduced HIF1-α protein abundance. Interestingly, HIF-1α mRNA levels were minimally affected, thus suggesting that Spry1KO might impact on HIF-1α expression post-translationally. IP-MS identified about 50 Spry1 protein partners, and most of them were mitochondrial. Importantly, western blot analysis of cytosolic and mitochondrial proteins revealed that Spry1 was largely expressed in CM cell lines irrespective of BRAF mutation. Conclusions. Altogether, these data lead us to speculate that Spry1 might play a role in mitochondria homeostasis, thus impacting on hypoxia and angiogenesis in CM.

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CHI3L1 promotes proliferation and metastasis of ovarian cancer cells

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