A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL‐13Rα2‐mediated JNK‐AP‐1 signals

Lee, Yong Sun; Yu, Ji Eun; Kim, Ki Cheon; Lee, Dong Hun; Son, Dong Ju; Lee, Hee Pom; Cho, Jungsook; Kim, Nam Du; Ham, Young Wan; Yun, Jaesuk; Han, Sang‐Bae; Hong, Jin Tae

doi:10.1002/1878-0261.13138

Cited by 18 publications

(9 citation statements)

References 37 publications

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“…8e ). Individual invasion program genes are coherently expressed in macrophages, only increase in non-responders, and include known invasion and metastasis mediators ( CTSL 5 9 , CTSD 60 , CTSB 61 , CHI3L1 62 , SPP1 63 , PLIN2 64 ). Moreover, the invasion program includes cholesterol metabolism genes ( APOE 65,66 , APOC1 67 , CYP27A1 68 , GPNMB 69 ), some which have been linked to the suppression of inflammatory cytokine release (IL-6, TNF-alpha).…”

Section: Resultsmentioning

confidence: 99%

Supervised discovery of interpretable gene programs from single-cell data

Kunes

Walle

Nawy

et al. 2022

Preprint

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Factor analysis can drive biological discovery by decomposing single-cell gene expression data into a minimal set of gene programs that correspond to processes executed by cells in a sample. However, matrix factorization methods are prone to technical artifacts and poor factor interpretability. We have developed Spectra, an algorithm that identifies user-provided gene programs, modifies them to dataset context as needed, and detects novel programs that together best explain expression covariation. Spectra overcomes the dominance of cell-type signals by modeling cell-type-specific programs, and can characterize interpretable cell states along a continuum. We show that it outperforms existing approaches in challenging tumor immune contexts; Spectra finds factors that change under immune checkpoint therapy, disentangles the highly correlated features of CD8+ T-cell tumor reactivity and exhaustion, finds a novel program that explains continuous macrophage state changes under therapy, and identifies cell-type-specific immune metabolic programs.

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Section: Resultsmentioning

confidence: 99%

Supervised discovery of interpretable gene programs from single-cell data

Kunes

Walle

Nawy

et al. 2022

Preprint

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“…Further progress in research on the direct interactions of CHI3L1 expression with the expression and activity of PD-L1 due to the detailed study of PD-L1 in the tumor pathology and the use of the knowledge about PD-L1 not only in immunotherapy but also in dynamic phototherapy may contribute to overcoming resistance to immunotherapies, chemotherapy, and radiotherapy [ 71 , 72 ]. Due to ongoing studies using molecules targeting CHI3L1 expression such as small molecules targeting YKL-40 and chitosan, our high-dimensional analysis demonstrating associations between CHI3L1 expression and processes related to immunosuppression and the tumor microenvironment in colorectal cancer may contribute to a more thorough understanding and shape further research on the role of CHI3L1 in the pathology of colorectal cancer [ 73 , 74 ].…”

Section: Discussionmentioning

confidence: 99%

Do Elevated YKL-40 Levels Drive the Immunosuppressive Tumor Microenvironment in Colorectal Cancer? Assessment of the Association of the Expression of YKL-40, MMP-8, IL17A, and PD-L1 with Coexisting Type 2 Diabetes, Obesity, and Active Smoking

Ochman

Mielcarska

Kula

et al. 2023

CIMB

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The influence of chitinase-3-like protein 1 (YKL-40 or CHI3L1) expression on the immunological properties of the tumor microenvironment, which may affect the effectiveness of immunotherapy, is currently not sufficiently understood in colorectal cancer (CRC). The aim of this study was to investigate the relationship between YKL-40 expression and the immunological properties of the tumor microenvironment in CRC. We performed in silico analysis, including analysis of immune cell infiltration scores and the immune landscape depending on YKL-40 expression, gene set enrichment analysis (GSEA), and analysis of three Gene Expression Omnibus (GEO) datasets. In 48 CRC tissue homogenates and the surgical margin, we analyzed the expression of YKL-40, MMP8, IL17A, and PD-L1. Moreover, we analyzed the expression of YKL-40 in tissue homogenates retrieved from patients with coexisting diabetes, obesity, and smoking. The expression of YKL-40 was significantly higher in CRC tumor tissue compared to healthy tissue and correlated with MMP-8, IL17A, and PD-L1 expression. In silico analysis revealed an association of YKL-40 with disease recurrence, and GSEA revealed a potential link between elevated YKL-40 expression and immunosuppressive properties of the tumor microenvironment in CRC.

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“…It is unknown which YKL-40-receptor binding is the one(s) leading to cancer-promoting effects observed in this and other pre-clinical studies. Recently, the chitin-binding domain was associated with the binding domain to IL13Rα2, suggesting that COS could block the interaction between YKL-40 and IL13Rα2 [ 45 ]. This could be one of the ways that COS exert their effects on tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Chitooligosaccharides Improve the Efficacy of Checkpoint Inhibitors in a Mouse Model of Lung Cancer

et al. 2022

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YKL-40 (also named chitinase 3 like-1 protein [CHI3L1]) is a secreted chitinase-like protein which is upregulated in cancers and suggested to have pro-tumorigenic activity. YKL-40 lacks enzymatic function, but it can bind carbohydrates such as chitin. Chitooligosaccharides (COS) derived from deacetylation and hydrolysis of chitin might be used for the blockade of YKL-40 function. Here, public single-cell RNA sequencing datasets were used to elucidate the cellular source of YKL-40 gene expression in human tumors. Fibroblasts and myeloid cells were the primary sources of YKL-40. Screening of YKL-40 gene expression in syngeneic mouse cancer models showed the highest expression in the Lewis lung carcinoma (LL2) model. LL2 was used to investigate COS monotherapy and combinations with immune checkpoint inhibitors (anti-PD-L1 and anti-CTLA-4) (ICIs) and radiotherapy (8 Gy × 3) (RT). COS tended to reduce plasma YKL-40 levels, but it did not affect tumor growth. LL2 showed minimal responses to ICIs, or to RT alone. Interestingly, ICIs combined with COS led to delayed tumor growth. RT also enhanced the efficacy of ICIs; however, the addition of COS did not further delay the tumor growth. COS may exert their anti-tumorigenic effects through the inhibition of YKL-40, but additional functions of COS should be investigated.

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A small molecule targeting CHI3L1 inhibits lung metastasis by blocking IL‐13Rα2‐mediated JNK‐AP‐1 signals

Cited by 18 publications

References 37 publications

Supervised discovery of interpretable gene programs from single-cell data

Supervised discovery of interpretable gene programs from single-cell data

Do Elevated YKL-40 Levels Drive the Immunosuppressive Tumor Microenvironment in Colorectal Cancer? Assessment of the Association of the Expression of YKL-40, MMP-8, IL17A, and PD-L1 with Coexisting Type 2 Diabetes, Obesity, and Active Smoking

Chitooligosaccharides Improve the Efficacy of Checkpoint Inhibitors in a Mouse Model of Lung Cancer

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