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DKN-01 Suppresses Gastric Cancer Progression Through Activating cGAS-STING Pathway to Block Macrophage M2
Xiaohuan Yang1, Yingying Qi1, Sisi Wang2
1Department of Ultrasound, Central Hospital Affiliated To Shandong First Medical University, Jinan, 250000, Shandong, China.
Abstract:
Dickkopf-1 (DKK1) is a secretory antagonist that can bind with the Wnt coreceptor to desensitize cells to canonical Wnt ligands. DKN-01 is a specific antibody targeting secreted DKK1, which has been investigated as a monotherapy or combination therapy for various malignant tumors, including gastric cancer (GC). Tumor-associated macrophages (TAMs) with high plasticity usually present M2 phenotype, which can promote tumor progression. The aim of this study was to investigate the effect of DKN-01 on macrophage polarization in GC and the underlying molecular mechanism. To ascertain the effect of DKN-01 on GC tumor growth, we established a tumor-bearing mouse model and found that DKN-01 treatment suppressed tumor growth efficiently. Through RNA-seq and pathway enrichment analysis, we identified that the differentially expressed genes after DKN-01 treatment are associated with tumor immune-related pathways. Macrophage polarization was assessed using immunohistochemistry and quantitative real-time polymerase chain reaction. DKN-01 and knockdown of DKK1 promoted M1 polarization and inhibited M2 polarization of macrophages, while DKK1 overexpression got the opposite results. Moreover, DKN-01 activated the cGAS/STING pathway, while the inactivation of cGAS-STING pathway using RU.521 reversed the inhibition of tumor growth in vivo and macrophage M2 polarization caused by DKN-01. This study reveals that DKN-01 suppresses GC tumor growth through activating cGAS-STING pathway to block macrophage M2 polarization.
Insights
DKN-01, an antibody targeting Dickkopf-1 (DKK1), suppresses gastric cancer growth by activating the cGAS/STING pathway. This action blocks tumor-promoting M2 macrophage polarization, offering a new therapeutic strategy.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Dickkopf-1 (DKK1) antagonizes Wnt signaling, promoting tumor growth.
- DKN-01 is an antibody targeting DKK1, explored for cancer therapy.
- Tumor-associated macrophages (TAMs) often exhibit an M2 phenotype, driving cancer progression.
Purpose of the Study:
- To investigate DKN-01's effect on macrophage polarization in gastric cancer (GC).
- To elucidate the molecular mechanisms underlying DKN-01's anti-tumor activity.
Main Methods:
- Established a GC tumor-bearing mouse model.
- Utilized RNA-sequencing (RNA-seq) and pathway enrichment analysis.
- Assessed macrophage polarization via immunohistochemistry and qPCR.
- Investigated the role of the cGAS/STING pathway.
Main Results:
- DKN-01 treatment significantly suppressed GC tumor growth.
- DKN-01 promoted M1 macrophage polarization and inhibited M2 polarization.
- DKN-01 activated the cGAS/STING pathway, which was crucial for its effects.
- Inactivating cGAS-STING reversed DKN-01's anti-tumor and anti-M2 polarization effects.
Conclusions:
- DKN-01 suppresses gastric cancer growth by activating the cGAS/STING pathway.
- This activation leads to the inhibition of pro-tumor M2 macrophage polarization.
- DKN-01 represents a potential therapeutic agent for gastric cancer by modulating the tumor immune microenvironment.
