Mitochondrial fusion heterogeneity drives bidirectional tumor phenotypic transition in combined hepatocellular–cholangiocarcinoma
Menée à l'aide de modèles murins et d'échantillons de cholangiocarcinomes hépatocellulaires d'origine humaine, cette étude met en évidence un mécanisme par lequel l'hétérogénéité de la fusion mitochondriale influence le phénotype tumoral
Combined hepatocellular-cholangiocarcinoma (cHC) is a prototypical heterogeneous tumor of monoclonal origin, characterized by an exceptionally poor prognosis. The mechanisms underlying its divergent phenotypes remain largely unknown. Here, we generated a mosaic pattern of mitochondrial fusion impairment in the mouse liver under tumor-promoting conditions and, unexpectedly, consistently observed the high incidence and reproducible development of cHC. Analysis of human cHC specimens revealed that intrahepatic cholangiocarcinoma-like cells exhibit more pronounced mitochondrial fusion defects than hepatocellular carcinoma-like cells. Remarkably, restoration of the mitochondrial fusion protein MFN1 effectively suppressed cHC formation. These results establish mitochondrial dynamics as a critical regulator of tumor cell phenotype, demonstrate a causal relationship between mitochondrial dysfunction and cHC pathogenesis, and provide mechanistic insights into lineage specification during tumorigenesis. 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.
Proceedings of the National Academy of Sciences , résumé, 2026