Lactate production by tumor-resident Staphylococcus promotes metastatic colonization in lung adenocarcinoma
Huan Yu, Yang Du, Yuling He, Yifan Sun, Junfeng Li, Bo Jia, Jiale Chen, Xinya Peng, Tongtong An, Jianjie Li, Yujia Chi, Man Wang, Lihua Cao, Yidi Tai, Xiaoyu Zhai, Reyizha Nuersulitan, Sheng Li, Nan Wu, Jia Wang, Hongchao Xiong, Shujie Wan, Jia-Ming Liu, Xuelian Yang, Xingsheng Hu, Dongmei Lin, Wei Sun, Yue Wang, Guo An, Xumeng Ji, Lingdong Kong, Lu Ding, Yunan Ma, Zhihua Tian, Bin Dong, Yujing Bi, Jianmin Wu, Ziping Wang
Abstract
The role of the lung microbiota in cancer remains unclear. Here, we reveal that Staphylococcus is selectively enriched in metastatic tumor lesions and is associated with tumor recurrence in lung cancer patients. Using patient-derived bacterial strains, we employ a combination of cell line, organoid, mouse allograft, and xenograft models to demonstrate that S. nepalensis and S. capitis promote the metastatic potential of lung cancer cells. Mechanistically, lactate secreted by S. nepalensis and S. capitis upregulates MCT1 expression in tumor cells, facilitating lactate uptake and activating pseudohypoxia signaling. These effects can be eliminated by knocking out the lactate-producing genes (D-lactate dehydrogenase [ddh]/L-lactate dehydrogenase [ldh]) in the bacterial strains. Furthermore, we show that inhibiting MCT1 attenuates Staphylococcus-induced tumor metastasis both in vitro and in vivo. Collectively, our results demonstrate that tumor-resident Staphylococcus species promote lung cancer metastasis by activating host pseudohypoxia signaling and further identify key regulators as potential targets for therapeutic development.