研究表明血管内皮（EC）除了作为物理载体运送血流，还存在其他促肿瘤机制。申请人前期通过构建EC与大肠癌细胞（CRC）共培养体系，首次发现EC调控CRC氧化磷酸化促进其增殖。文献报道氧化磷酸化对大肠癌发生发展至关重要。因此，研究EC调控CRC氧化磷酸化的机制具有重要的科学意义。申请人进一步鉴定了EC促CRC氧化磷酸化的关键成分-外泌体及其组分，筛选到新分子LYRM2；LYRM2定位于线粒体的内膜及基质，促进了CRC的氧化磷酸化。为此我们提出假说：EC通过外泌体转运LYRM2促进CRC的氧化磷酸化。本课题拟在前期基础上，利用外泌体标记、蛋白体内示踪、CRISPR技术，从动物、细胞、分子水平上：完善EC促CRC氧化磷酸化的新功能；鉴定EC转运LYRM2促进CRC中氧化磷酸化的新机制；探讨靶向干预EC中LYRM2的潜在应用价值，为大肠癌的治疗提供新靶点，并为干预肿瘤氧化磷酸化提供新的思路。

Evidence suggests that vascular endothelial cells (EC) have other mechanisms to promote tumor development except serving as a physical carrier of blood flow. The applicant preliminarily discovered that EC regulate the oxidative phosphorylation of colorectal cancer cells (CRC) and promote its proliferation by a co-culture system. It has been reported that oxidative phosphorylation is essential for the development of colorectal cancer. Therefore, it is of great scientific significance to study the mechanism by which EC regulate the oxidative phosphorylation of CRC. Applicant further analyzed the components of exosome by mass spectrometry and screened a new molecule LYRM2. We further found that LYRM2 located in the inner membrane and matrix of mitochondria, and promoted oxidative phosphorylation in CRCs. To this end, we propose the following hypothesis: EC-derived Exosome transfers LYRM2 to CRC → LYRM2 is upregulated in CRC →oxidative phosphorylation is increased in CRC. Using exosome labeling, in vivo tracing and CRISPR technologies, we can 1) identify the biological function of EC in promoting oxidative phosphorylation of CRC by releasing exosome; 2) identify the mechanisms of EC transferring LYRM2 and promoting oxidative phosphorylation of CRC; 3) block LYRM2 in EC using transgenic mice model to explore its potential translational value. By completing this project, we will provide a new target for the treatment of CRC, and open up new directions and thoughts for the metabolic intervention of malignant tumors.