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

Abstract

Background and AimsMetabolic and transcriptional programs respond to extracellular matrix (ECM)-derived cues in complex environments, such as the tumor microenvironment (TME). Here, we demonstrate how lysyl oxidase (LOX), a known factor in collagen crosslinking, contributes to the development and progression of cholangiocarcinoma (CCA). MethodsTranscriptomes of 209 human CCA tumors,143 surrounding tissues, and single-cell data from 30 patients were analyzed. The recombinant protein (rLOX) 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. ResultsWe traced LOX expression to hepatic stellate cells (HSCs) and specifically HSC-derived inflammatory cancer-associated fibroblasts (iCAF), showing that CAF-driven LOX increases oxidative phosphorylation (OXPHOS), metabolic fitness of CCA, and regulates the mitochondrial function through TFAM. Inhibiting LOX activity in vivo impedes CCA development and progression. Our work highlights that LOX alters TME-directed transcriptional reprogramming of CCA cells by facilitating the expression of the OXPHOS pathway and by increasing stemness and mobility. ConclusionIncreased LOX is driven by stromal iCAFs and correlates with diminished survival of patients with CCA. Modulating the LOX activity can serve as a novel TME-directed therapeutic strategy in bile duct pathologies.