Beyond mitochondrial transfer, cell fusion rescues metabolic dysfunction and boosts malignancy in adenoid cystic carcinoma
Xianghe Qiao,
Nengwen Huang,
Wanrong Meng,
Yunkun Liu,
Jinjin Li,
Chunjie Li,
Wenxuan Wang,
Yi Lai,
Yongjiang Zhao,
Zhongkai Ma,
Jingya Li,
Xuan Zhang,
Zhijie Weng,
Chenzhou Wu,
Longjiang Li,
Bo Li
Affiliations
Xianghe Qiao
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Nengwen Huang
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Wanrong Meng
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Yunkun Liu
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Jinjin Li
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
Chunjie Li
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Wenxuan Wang
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Yi Lai
Department of Medical Genetics/Prenatal Diagnostic Center, West China Second Hospital, Sichuan University, Chengdu 610041, China
Yongjiang Zhao
Genetics and Prenatal Diagnostic Center, The First Affiliated Hospital of Zhengzhou University, Henan Engineering Research Center for Gene Editing of Human Genetic Disease, Zhengzhou 450052, China
Zhongkai Ma
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Jingya Li
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Xuan Zhang
Department of Medical Genetics/Prenatal Diagnostic Center, West China Second Hospital, Sichuan University, Chengdu 610041, China
Zhijie Weng
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Chenzhou Wu
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
Longjiang Li
Department of Head and Neck Oncology, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Corresponding author
Bo Li
State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; Corresponding author
Summary: Cancer cells with mitochondrial dysfunction can be rescued by cells in the tumor microenvironment. Using human adenoid cystic carcinoma cell lines and fibroblasts, we find that mitochondrial transfer occurs not only between human cells but also between human and mouse cells both in vitro and in vivo. Intriguingly, spontaneous cell fusion between cancer cells and fibroblasts could also emerge; specific chromosome loss might be essential for nucleus reorganization and the post-hybrid selection process. Both mitochondrial transfer through tunneling nanotubes (TNTs) and cell fusion “selectively” revive cancer cells, with mitochondrial dysfunction as a key motivator. Beyond mitochondrial transfer, cell fusion significantly enhances cancer malignancy and promotes epithelial-mesenchymal transition. Mechanistically, mitochondrial dysfunction in cancer cells causes L-lactate secretion to attract fibroblasts to extend TNTs and TMEM16F-mediated phosphatidylserine externalization, facilitating TNT formation and cell-membrane fusion. Our findings offer insights into mitochondrial transfer and cell fusion, highlighting potential cancer therapy targets.
