Lactate accumulation drives hepatocellular carcinoma metastasis through facilitating tumor-derived exosome biogenesis by Rab7A lactylation
Chenhao Jiang, Xinyi He, Xialin Chen, Jianyang Huang, Yasong Liu, Jianhao Zhang, Huaxin Chen, Xin Sui, Xing Lv, Xuegang Zhao, Cuicui Xiao, Jiaqi Xiao, Jiebin Zhang, Tongyu Lu, Haitian Chen, Haibo Li, Hongmiao Wang, Guo Lv, Linsen Ye, Rong Li, Jun Zheng, Jiaxi Yao, Yinqian Kang, Tao Wang, Hua Li, Jiancheng Wang, Yingcai Zhang, Guihua Chen, Jianye Cai, Andy Peng Xiang, Yang Yang
Abstract
Previous studies have demonstrated that lactate accumulation, a common hallmark for metabolic deprivation in solid tumors, could actively drive tumor invasion and metastasis. However, whether lactate influences the biogenesis of tumor-derived exosomes (TDEs), the prerequisite for distant metastasis formation, remains unknown. Here, we demonstrated that extracellular lactate, after taken up by tumor cells via lactate transporter MCT1, drove the release of TDE mainly through facilitating multivesicular body (MVB) trafficking towards plasma membrane instead of lysosome. Mechanistically, lactate promoted p300-mediated Rab7A lactylation, which hereafter inhibited its GTPase activity and promoted MVB docking with plasma membrane. Moreover, lactate administration enriched integrin β4 and ECM remodeling-related proteins in TDE cargos, which promoted pulmonary pre-metastatic niche formation. Combinatorial inhibition of MCT1 and p300 significantly abrogated HCC metastasis in a clinical-relevant PDX model. In summary, we demonstrated that lactate promote TDE biogenesis and HCC pulmonary metastasis, and proposed a potential clinical strategy targeting TDEs to prevent HCC metastasis.