CXCR7偏向信号转导通过上调外泌体miRNAs促进结直肠癌肺转移前微环境重塑的分子机制及药物新靶标研究

临床表明结直肠癌最常见转移部位是肝和肺，是导致患者死亡的主要原因。CXCL12/CXCR4激活与结直肠癌肝转移有关，而新近发现CXCL12的另一个受体CXCR7与结直肠癌肺转移相关，然而机制不清。本项目拟从肿瘤微环境视角，探索CXCL12/CXCR7偏向激活的结直肠癌细胞通过外泌体包裹miRNAs促进微环境肿瘤相关成纤维细胞(CAFs)激活，重塑肺转移前微环境的分子机制。以高通量miRNAs测序为切入点，拟在肿瘤临床样本、小鼠动物模型、细胞分子水平阐明高表达CXCR7结肠癌细胞通过上调外泌体miR-155-5p、miR-146a-5p激活CAFs的机制，更重要的是，首次提出CXCL12/CXCR7偏向信号激活通过招募β-arrestin 1促进YAP1核转位上调外泌体miRNAs的新机制，揭示外泌体miRNAs促进肿瘤转移的信使作用，为抑制结直肠癌肺转移和精准医疗提供新靶标和理论依据。

The most common metastatic sites of colorectal cancer are liver and lung, which is the leading cause of death in colon cancer patients. CXCL12/CXCR4 activation is associated with liver metastasis of colorectal cancer, while CXCR7, another receptor of CXCL12, has recently been found to be related to lung metastasis of colorectal cancer, but the mechanism is unclear. From the perspective of tumor microenvironment, this project aims to explore the new mechanism of CXCL12/CXCR7 biased signaling transduction promoting the activation of cancer-associated fibroblasts (CAFs) in the tumor microenvironment through exosome-encapsulated miRNAs and thereby promoting lung metastasis of colorectal cancer. Taking high-throughput miRNAs sequencing as the starting point, we elucidated the molecular mechanism of CXCR7-overexpressing colorectal cancer cells promoting the activation of CAFs by upregulating exosomal miR-155-5p and miR-146a-5p using clinical tumor samples, animal models and cell lines. More importantly, we first proposed that CXCL12/CXCR7 biased signal activation promoted YAP1 nuclear translocation by recruiting β-arrestin 1, through which exosomal miRNAs were upregulated. These results reveal the messenger effect of exosomal miRNAs in promoting tumor metastasis, and provide new targets and theoretical evidence for inhibiting organotropic lung metastasis of colorectal cancer and precision medicine-guided treatments.