Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Pathology, Soochow University Medical School, Suzhou, China.
Cell Metab. 2024 Mar 5;36(3):541-556.e9. doi: 10.1016/j.cmet.2023.12.020. Epub 2024 Jan 16.
The roles of platelets/megakaryocytes (MKs), the key components in the blood system, in the tumor microenvironment and antitumor immunity are unclear. In patients with colorectal cancer, the number of platelets was significantly increased in patients with metastasis, and Erbin expression was highly expressed in platelets from patients with metastases. Moreover, Erbin knockout in platelets/MKs suppressed lung metastasis in mice and promoted aggregations of platelets. Mechanistically, Erbin-deficient platelets have increasing mitochondrial oxidative phosphorylation and secrete lipid metabolites like acyl-carnitine (Acar) by abolishing interaction with prothrombotic protein ESAM. Notably, Acar enhanced the activity of mitochondrial electron transport chain complex and mitochondrial oxidative phosphorylation in B cells by acetylation of H3K27 epigenetically. Targeting Erbin in platelets/MKs by a nanovesicle system dramatically attenuated lung metastasis in mice in vivo. Our study identifies an Erbin-mitochondria axis in platelets/MKs, which suppresses B cell-mediated antitumor immunity, suggesting a new way for the treatment of metastasis.
血小板/巨核细胞（MKs）在肿瘤微环境和抗肿瘤免疫中的作用尚不清楚。在结直肠癌患者中，转移患者的血小板数量明显增加，转移患者的血小板中 Erbin 表达高度表达。此外，血小板/MKs 中的 Erbin 敲除抑制了小鼠的肺转移，并促进了血小板的聚集。从机制上讲，缺乏 Erbin 的血小板通过废除与促血栓形成蛋白 ESAM 的相互作用，增加线粒体氧化磷酸化并分泌酰基辅酶 A（Acar）等脂质代谢物。值得注意的是，Acar 通过组蛋白 H3K27 的乙酰化在体外乙酰化 B 细胞中线粒体电子传递链复合物和线粒体氧化磷酸化的活性。通过纳米囊泡系统靶向血小板/MKs 中的 Erbin，可显著减弱小鼠体内的肺转移。我们的研究确定了血小板/MKs 中的 Erbin-线粒体轴，该轴抑制了 B 细胞介导的抗肿瘤免疫，为治疗转移提供了一种新方法。
