Mitochondrial fusion heterogeneity drives bidirectional tumor phenotypic transition in combined hepatocellular–cholangiocarcinoma
Abstract
Dysregulation of mitochondrial dynamics modulates malignant cell fate; however, the substantial heterogeneity in mitochondrial dynamics among tumor cells within individual tumor nodules and the resultant functional consequences remain inadequately characterized. In this study, we induced mosaic impairment of mitochondrial fusion in mouse liver under tumorigenic conditions and unexpectedly identified the formation of combined hepatocellular-cholangiocarcinoma (cHC), a monoclonal tumor displaying features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Restoration of the mitochondrial fusion protein MFN1 effectively suppressed cHC development. Analysis of human cHC samples revealed that ICC-like cells exhibit more pronounced mitochondrial fusion impairment compared to HCC-like cells. Mechanistically, increasing impairment of mitochondrial fusion resulted in a dose-dependent elevation of reactive oxygen species (ROS). Low levels of ROS upregulated HNF4α, promoting HCC-like differentiation, whereas high ROS levels activated HES1, facilitating ICC-like differentiation. Collectively, these results demonstrate that heterogeneity in mitochondrial dynamics is a critical determinant of cHC path-ogenesis.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Lin Chen
Dalin Wang
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University
Weidong Qin
Department of Health Statistics, School of Preventive Medicine, Fourth Military Medical University
Gang Wang
Dan Wu
Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, State Key Laboratory Breeding Base of Eco-Environments and Bio-Resources of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University
Jiaying Li
Xingchen Wang
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University
Yinping Wang
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University
Xiacheng Sun
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University
Jing Zhao
Shanshan Guo
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University
Lele Ji
National Demonstration Center for Experimental Basic Medical Science Education, Fourth Military Medical University
Jiming Tian
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University
Rui Ding
Yongzhan Nie
National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University
Jinliang Xing
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University
Qichao Huang
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Physiology and Pathophysiology, Fourth Military Medical University