靶向circ-0034880富集的肿瘤细胞外囊泡，阻止SPP1高CD206+促肿瘤巨噬细胞介导的结直肠癌肝转移前转移龛形成

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2024-08-20 DOI:10.1186/s12943-024-02086-9

Jing Zhou, Qing Song, Haoze Li, Yicun Han, Yunzhou Pu, Ling Li, Wenqing Rong, Xiaodie Liu, Ziyuan Wang, Jian Sun, Yuqing Song, Xueyan Hu, Guanghao Zhu, Huirong Zhu, Liu Yang, Guangbo Ge, Hongshan Li, Qing Ji

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引用次数: 0

摘要

原发肿瘤细胞与远端器官的免疫细胞或基质细胞之间的信息传递是形成转移前生态位（PMN）的关键因素。了解这一机制对于制定有效的肿瘤转移治疗策略至关重要。我们的研究旨在证明一个假设，即circ-0034880富集的肿瘤源性细胞外囊泡（TEVs）介导了PMN和结直肠癌肝转移（CRLM）的形成，而靶向circ-0034880富集的TEVs可能是针对PMN形成和CRLM的有效治疗策略。我们利用 qPCR 和 FISH 技术测定了人 CRC 血浆、原发 CRC 组织和肝转移组织中 circRNAs 的表达水平。此外，我们还利用免疫荧光、RNA测序和体内实验评估了circ-0034880富集的TEVs对PMN形成和CRC转移的影响机制。应用DARTS、CETSA和计算对接模型探讨了人参皂苷Rb1阻碍PMN形成的药理作用。我们发现circ-0034880高度富集于CRC患者的血浆细胞外囊泡（EVs）中，并与CRLM密切相关。在功能上，circ-0034880富集的TEV通过血液进入肝脏组织并被肝脏中的巨噬细胞吸收。从机理上讲，TEV释放的circ-0034880增强了SPP1高CD206+亲肿瘤巨噬细胞的活化，重塑了支持转移的宿主基质微环境，促进了肿瘤的明显转移。重要的是，我们的机理研究结果使我们发现，天然产物人参皂苷 Rb1 通过减少 circ-0034880 的生物生成，阻碍了 SPP1highCD206+ 亲肿瘤巨噬细胞的活化，从而抑制了 PMN 的形成并抑制了 CRLM。富含circ-0034880的TEV可促进原发性肿瘤细胞与SPP1highCD206+原癌巨噬细胞之间的强烈相互作用，促进PMN的形成和CRLM。这些发现表明，人参皂苷 Rb1 有可能作为一种替代治疗药物，重塑 PMN 的形成并预防 CRLM。

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

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 SPP1highCD206+ pro-tumor macrophages, reshaping the metastasis-supportive host stromal microenvironment and promoting overt metastasis. Importantly, our mechanistic findings led us to discover that the natural product Ginsenoside Rb1 impeded the activation of SPP1highCD206+ pro-tumor macrophages by reducing circ-0034880 biogenesis, thereby suppressing PMN formation and inhibiting CRLM. Circ-0034880-enriched TEVs facilitate strong interaction between primary tumor cells and SPP1highCD206+ pro-tumor macrophages, promoting PMN formation and CRLM. These findings suggest the potential of using Ginsenoside Rb1 as an alternative therapeutic agent to reshape PMN formation and prevent CRLM.

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.