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Endothelial AGO1 deficiency reduces breast cancer burden in mice
Xuejing Liu1, Alonso Tapia1,2, Dongqiang Yuan1
1Department of Diabetes Complications and Metabolism, Beckman Research Institute, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA.
Abstract:
Endothelial cells (ECs) are crucial in cancer development and progression, partly by regulating tumor angiogenesis and immune modulation. As a key component of the RNA-induced silencing complex, Argonaute 1 (AGO1) regulates tumor biology, yet the specific function of AGO1 within ECs in the tumor microenvironment remains undefined. Here, we investigated the effects of endothelial-specific AGO1 knockout (EC-AGO1-KO) on tumor vascularization and immune regulation in a mouse syngeneic breast cancer model induced by E0771 cells. EC-AGO1-KO mice exhibited significantly reduced tumor burden compared to their wild-type (WT) littermates, accompanied by reduced vascularization and enhanced immune cell infiltration. Histological and single-cell RNA sequencing analyses revealed increased infiltration of CD8⁺ T cells and macrophages in EC-AGO1-KO tumors, indicative of an immunostimulatory microenvironment. In vitro, AGO1 knockdown in mouse ECs co-cultured with E0771 tumor cells led to higher levels of Cxcl10 and Vcam1 expression, suggesting a pro-inflammatory and leukocyte-recruiting effect. Together, these findings identify endothelial AGO1 as a key regulator of tumor vasculature and immune homeostasis in breast cancer, suggesting that targeting endothelial AGO1 may represent a novel therapeutic strategy to modulate tumor vasculature while enhancing anti-tumor immunity.
Insights
Removing Argonaute 1 (AGO1) from endothelial cells reduced breast cancer growth by limiting tumor vascularization and boosting anti-tumor immunity. This suggests targeting endothelial AGO1 may improve cancer therapies.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Endothelial cells (ECs) play vital roles in cancer progression, influencing tumor angiogenesis and immune responses.
- Argonaute 1 (AGO1), a key RNA-induced silencing complex component, impacts tumor biology, but its function in tumor microenvironment ECs is unclear.
Purpose of the Study:
- To investigate the role of endothelial AGO1 in regulating tumor vascularization and immune modulation within the tumor microenvironment.
- To determine the therapeutic potential of targeting endothelial AGO1 in breast cancer.
Main Methods:
- Generated endothelial-specific AGO1 knockout (EC-AGO1-KO) mice using a syngeneic E0771 breast cancer model.
- Performed histological analysis and single-cell RNA sequencing (scRNA-seq) on tumors from EC-AGO1-KO and wild-type (WT) mice.
- Conducted in vitro experiments involving AGO1 knockdown in ECs co-cultured with tumor cells.
Main Results:
- EC-AGO1-KO mice showed significantly reduced tumor burden compared to WT littermates.
- Tumors in EC-AGO1-KO mice exhibited decreased vascularization and increased infiltration of CD8+ T cells and macrophages.
- In vitro studies revealed that AGO1 knockdown in ECs increased Cxcl10 and Vcam1 expression, promoting inflammation and leukocyte recruitment.
Conclusions:
- Endothelial AGO1 is a critical regulator of tumor vascularization and immune homeostasis in breast cancer.
- Targeting endothelial AGO1 may offer a novel therapeutic strategy to simultaneously modify tumor vasculature and enhance anti-tumor immunity.
