Targeting circ-0034880-enriched tumor extracellular vesicles to impede SPP1highCD206+ pro-tumor macrophages mediated pre-metastatic niche formation in colorectal cancer liver metastasis

作者：Jing Zhou, Qing Song, Haoze Li, Haoze Li, Yicun Han, Yunzhou Pu, Ling Li, Wenqing Rong, Xiaodie Liu, Ziyuan Wang, Jian Sun, Yuqing Song, Guanghao Zhu, Huirong Zhu, Huirong Zhu, Liu Yang, Guangbo Ge, Qing Ji, Hongshan Li, Qing Ji · 发表于：Molecular Cancer · 年份：2024 · DOI：10.1186/s12943-024-02086-9 · 被引用次数：55 · 研究领域：Circular RNAs in diseases、Extracellular vesicles in disease、Ferroptosis and cancer prognosis

Information transmission between primary tumor cells and immunocytes or stromal cells in distal organs is a critical factor in the formation of pre-metastatic niche (PMN). Understanding this mechanism is essential for developing effective therapeutic strategy against tumor metastasis. Our study aims to prove the hypothesis that circ-0034880-enriched tumor-derived extracellular vesicles (TEVs) mediate the formation of PMN and colorectal cancer liver metastasis (CRLM), and targeting circ-0034880-enriched TEVs might be an effective therapeutic strategy against PMN formation and CRLM. We utilized qPCR and FISH to measure circRNAs expression levels in human CRC plasma, primary CRC tissues, and liver metastatic tissues. Additionally, we employed immunofluorescence, RNA sequencing, and in vivo experiments to assess the effect mechanism of circ-0034880-enriched TEVs on PMN formation and CRC metastasis. DARTS, CETSA and computational docking modeling were applied to explore the pharmacological effects of Ginsenoside Rb1 in impeding PMN formation. We found that circ-0034880 was highly enriched in plasma extracellular vesicles (EVs) derived from CRC patients and closely associated with CRLM. Functionally, circ-0034880-enriched TEVs entered the liver tissues and were absorbed by macrophages in the liver through bloodstream. Mechanically, TEVs-released circ-0034880 enhanced the activation of SPP1 high CD206 + pro-tumor macrophages, reshaping the metastasis-supportive host stromal microenv...