Lewinska, Monika and Zhuravleva, Ekaterina and Satriano, Letizia and Martinez, Marta B. and Bhatt, Deepak K. and Oliveira, Douglas V. N. P. and Antoku, Yasuko and Keggenhoff, Friederike L. and Castven, Darko and Marquardt, Jens U. and Matter, Matthias S. and Erler, Janine T. and Oliveira, Rui C. and Aldana, Blanca I. and Al-Abdulla, Ruba and Perugorria, Maria J. and Calvisi, Diego F. and Perez, Luis Arnes and Rodrigues, Pedro M. and Labiano, Ibone and Banales, Jesus M. and Andersen, Jesper B. (2024) Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma. GASTROENTEROLOGY, 166 (5). ISSN 0016-5085, 1528-0012
Full text not available from this repository. (Request a copy)Abstract
BACKGROUND & AIMS: 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). METHODS: 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 fi tness, 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. RESULTS: We traced LOX expression to hepatic stellate cells and speci fi cally hepatic stellate cell - derived infl ammatory cancer -associated fi broblasts and found that cancer -associated fi broblast - driven LOX increases oxidative phosphorylation and metabolic fi tness 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. CONCLUSIONS: Increased LOX is driven by stromal in fl ammatory cancer -associated fi broblasts 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEPATOCELLULAR-CARCINOMA; TUMOR MICROENVIRONMENT; THERAPEUTIC TARGETS; INHIBITION; GROWTH; CELLS; CONTRIBUTES; PROGNOSIS; SUBTYPES; Cholangiocarcinoma; Tumor Microenvironment; Extracellular Matrix; Lysyl Oxidase |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Jan 2026 08:18 |
| Last Modified: | 16 Jan 2026 08:18 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65418 |
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