Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma

Metabolic and transcriptional programs respond to extracellular matrix–derived cues in complex environments, such as the tumor microenvironment. Here, we demonstrate how lysyl oxidase (LOX), a known factor in collagen crosslinking, contributes to the development and progression of cholangiocarcinoma (CCA). Transcriptomes of 209 human CCA tumors, 143 surrounding tissues, and single-cell data from 30 patients were analyzed. The recombinant protein and a small molecule inhibitor of the LOX activity were used on primary patient-derived CCA cultures to establish the role of LOX in migration, proliferation, colony formation, metabolic fitness, and the LOX interactome. The oncogenic role of LOX was further investigated by RNAscope and in vivo using the AKT/NICD genetically engineered murine CCA model. We traced LOX expression to hepatic stellate cells and specifically hepatic stellate cell–derived inflammatory cancer-associated fibroblasts and found that cancer-associated fibroblast–driven LOX increases oxidative phosphorylation and metabolic fitness of CCA, and regulates mitochondrial function through transcription factor A, mitochondrial. Inhibiting LOX activity in vivo impedes CCA development and progression. Our work highlights that LOX alters tumor microenvironment–directed transcriptional reprogramming of CCA cells by facilitating the expression of the oxidative phosphorylation pathway and by increasing stemness and mobility. Increased LOX is driven by stromal inflammatory cancer-associated fibroblasts and correlates with diminished survival of patients with CCA. Modulating the LOX activity can serve as a novel tumor microenvironment–directed therapeutic strategy in bile duct pathologies. [Display omitted] Lysyl oxidase expression is enhanced in cholangiocarcinoma tumors and predictive of poor survival. Lysyl oxidase is found mainly in cancer-associated fibroblasts, resident stromal cells responsible for shaping the tumor microenvironment. Lysyl oxidase inactivation in vivo shows diminished cholangiocarcinoma burden in murine livers. Therefore, targeting lysyl oxidase may be a promising therapeutic strategy in cholangiocarcinoma.